Bufei Huoxue Capsule Attenuates PM2.5-Induced …downloads.hindawi.com/journals/ecam/2017/1575793.pdf · COPD EGR1 CXCR2 CYP1A1 EGLN2 EGFR Immunoglobulin PDE4A IL33 IL32 IL22 MMP9

Research ArticleBufei Huoxue Capsule Attenuates PM25-InducedPulmonary Inflammation in Mice

Yue Jing12 Hongchun Zhang2 Zhe Cai3 Yukun Zhao4 YeWu56 Xuan Zheng5

Ying Liu7 Yuying Qin18 Mingjie Gu1 and Jin Jin1

1Graduate School Beijing University of Chinese Medicine 11 North 3rd Ring East Road Chaoyang DistrictBeijing 100029 China2National Clinical Research Center for Respiratory Diseases and Traditional Chinese Medicine Department of Pulmonary DiseasesChina-Japan Friendship Hospital 2 Yinghua Dongjie Hepingli Chaoyang District Beijing 100029 China3Clinical Research Institute China-Japan Friendship Hospital 2 Yinghua Dongjie Hepingli Chaoyang DistrictBeijing 100029 China4Institute of Basic Theory for Chinese Medicine China Academy of Chinese Medical Science 16 Dongzhimennei NanxiaojieDongcheng District Beijing 100700 China5School of Environment State Key Joint Laboratory of Environment Simulation and Pollution ControlTsinghua University Beijing 100084 China6State Environmental Protection Key Laboratory of Sources and Control of Air Pollution ComplexBeijing 100084 China7Geriatrics China-Japan Friendship Hospital 2 Yinghua Dongjie Hepingli Chaoyang District Beijing 100029 China8Zhengzhou Hospital of Traditional Chinese Medicine Zhengzhou City Henan Province 450008 China

Correspondence should be addressed to Hongchun Zhang hongchunzyahoocom

Received 21 October 2016 Revised 4 January 2017 Accepted 29 January 2017 Published 27 February 2017

Academic Editor Jae Youl Cho

Copyright copy 2017 Yue Jing et al This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Atmospheric fine particulate matter 25 (PM 25) may carry many toxic substances on its surface and this may pose a publichealth threat Epidemiological research indicates that cumulative ambient PM25 is correlated to morbidity and mortality due topulmonary and cardiovascular diseases and cancer Mitigating the toxic effects of PM25 is therefore highly desired Bufei Huoxue(BFHX) capsules have been used in China to treat pulmonary heart disease (cor pulmonale)Thus we assessed the effects of BFHXcapsules on PM25-induced pulmonary inflammation and the underlying mechanisms of action Using Polysearch and Cytoscape321 software pharmacological targets of BFHX capsules in atmospheric PM25-related respiratory disorders were predictedand found to be related to biological pathways of inflammation and immune function In a mouse model of PM25-inducedinflammation established with intranasal instillation of PM25 suspension BFHX significantly reduced pathological response andinflammatorymediators including IL-4 IL-6 IL-10 IL-8 TNF-120572 and IL-1120573 BFHX also reduced keratinocyte growth factor (KGF)secretory immunoglobulin A (sIgA) and collagen fibers deposition in lung and improved lung function Thus BFHX reducedpathological responses induced by PM25 possibly via regulation of inflammatory mediators in mouse lungs

1 Introduction

China has a substantial air pollution problem and of hazeepisodes correlate to atmospheric particulate matter abun-dance [1ndash3] Fine particulatematter with nominalmean aero-dynamic diameters of 25 120583m or less is defined as particulate

matter 25 (PM25) Although PM25 particles are small andbuoyant they carry many toxic substances on their surfaceand they can ldquohangrdquo in the atmosphere for some time andtravel great distances [4]Much epidemiological data indicatethat cumulative ambient fine particulate matter correlates tomorbidity of and mortality from pulmonary cardiovascular

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2017 Article ID 1575793 12 pageshttpsdoiorg10115520171575793

2 Evidence-Based Complementary and Alternative Medicine

diseases and cancer [5ndash12] and these problems represent asignificant social and economic burden

Based on systems biology and pharmacology networkpharmacology leverages network analysis and screens nodesto identify proteins critical to a disease for drug design[13 14] Network pharmacology can be used to investigatesynergism of multicomponent drugs to identify high efficacyand low toxicity agents with multiple targets [15 16] Chineseherbal formulas often have numerous targets and are com-prised of many substances so network pharmacologymay beuseful for studying traditional Chinese medicine [17 18]

Bufei Huoxue (BFHX) capsules contain three commonChinese herbal products Astragalus radix paeoniae rubraand Psoralea corylifolia and have been approved by the ChinaFood and Drug Administration (Number Z20030063) forthe treatment of pulmonary heart disease Clinical studiessuggest that these compounds improve pulmonary ventila-tion function and reduce silicosis and lung inflammation[19ndash21] Thus we studied BFHX capsules and PM25-relatedrespiratory disease using a network pharmacology platformThe effects of BFHX capsules on PM25-induced pulmonaryinflammation were evaluated and the underlying mecha-nisms of action were investigated in mice

2 Materials and Methods

21 PM25-Related Diseases PM25-related diseases wereidentified using Polysearch System (httpwishartbiologyualbertacapolysearchindexhtm) a web-based text-min-ing system for extracting relationships among human dis-eases genes drugs and metabolism PM25-related dis-eases were searched and extracted statements were manuallyscreened According to 119885-values the top 10 diseases wereselected for further study

22 Prediction of Disease Pathways and BFHX Targets Alltarget genes or proteins for each BFHX component (Astra-galus radix paeoniae rubra and Psoralea corylifolia) wereobtained using Polysearch and diseases were selected frompredictions based on keywords Targets were networked andvisualized using Cytoscape 321 software Drug- and disease-related targets were merged using Merge to screen key targetproteins

23 PM25 Mouse Model and Drug Intervention

231 PM25 Sampling and Suspension Preparation PM25samples were collected from three sites in Beijing in thesummer and winter seasons of 2011 and 2012 The three siteswere a roadside site located 2m from the curb of the North4th Ring Road an urban site on the campus of Tsinghua Uni-versity and a rural site situated in the countryside of MiyunSampling was conducted by Anderson particulate samplerHBL-GUV (Thermo Fisher Waltham MA) equipped witha PTFE membrane for two consecutive weeks [22] At theend of sample collection the PTFE membrane carryingPM25 was cut into 1 times 3 cm pieces and placed in ultrapurewater Particles were eluted three times under ultrasonic

oscillation 40min each Liquid containing the particulatematter was filtered through six layers of sterile gauze andcentrifuged at 12000 rpm at 4∘C for 30min The lower layerof the suspension was collected and vacuum-freeze dried toyield PM25 particles which were then stored at minus20∘C Tomake a stock solution PM25 particles were weighed andsuspended in saline at the desired concentrations after beingultrasonicated for 15min and sterilized Samples were storedat 4∘C Detailedmethods can be found in related papers by usand other authors [23 24]

232 Drugs BFHX capsules were provided by Lei Yun ShangPharmaceutical Limited (Suzhou Jiangsu China) The drypowder was taken from the capsules and suspended indistilled water The mixture was stored at 4∘C

233 Animals Adult female ICR mice (Beijing HFKBiotechnology Co Ltd China 22ndash26 g) were housed inseparate cages with food and water freely available understandard laboratory conditions of 22ndash28∘C and relativehumidity of 50ndash60 with a 12 h light12 h dark cycle Animaltreatment and maintenance were performed in accordancewith requirements of and the study protocol was approvedby the institutional animal care and use committee at theChina-Japan Friendship Hospital in Beijing (Permit 150202) All efforts were made to minimize suffering

Sixty ICR female mice were randomized into 3 groupsnormal controls PM25 exposure and BFHX interventiongroups (119873 = 20group) Controls were given an intranasalinstillation of saline (20120583lmouse) on days 1 8 15 and 22ThePM25 exposure group was given an intranasal instillation ofPM25 suspension (40mgkg 20 120583lmouse) on days 1 8 15and 22 and each received oral saline (02mlmouseday) fromdays 1 to 22 The BFHX intervention group was treated aswas the PM25 exposure group except that BFHX (082 gkg02mlmouseday) instead of saline was given daily Animalswere sacrificed 48 h after the last treatment

24 Lung Function Mice were anesthetized with 2 pento-barbital (04ml40 g ip) and secured in a supine position tobe orotracheally intubated Then mice were transferred toa plethysmography platform and lung function analysis wasmeasured lung include inspiratory resistance (RL) expira-tory resistance (RE) dynamic lung compliance (Cdyn) andpeak expiratory flow (PEF) using an AniRes2005 apparatus(Beilanbo Science and Technology Co Ltd Beijing China)

25 Lung Histology Mice were sacrificed and subjected tothoracotomy with lung resectionThe left lung lobe was fixedin 10 formalin for 24 h and then dehydrated embeddedin paraffin and sectioned Sections were stained with hema-toxylin and eosin (HampE) according to the routine stainingmethod and observed under an optical microscopeThe rightlung lobe was homogenized for molecular studies

26 Masson Staining Lung collagen content was quantifiedwith Masson trichrome staining Paraffin sections were firstdewaxed followed by washing with tap and then distilled

Evidence-Based Complementary and Alternative Medicine 3

water Sections were then stained to identify nuclei withRegaud or Weigert hematoxylin for 5ndash10min After fullywashing with water slides were washed with distilled waterand treated with Ponceau Masson Acid fuchsin solutionfor 5ndash10min Sections were then briefly immersed in a 2aqueous acetic acid solution and then treated with 1 phos-phomolybdic acid for 3ndash5min followed by direct stainingwith aniline blue or light green liquid dye for 5min Aftera brief Immersion in 02 acetic acid sections were treatedwith 95 alcohol ethanol and transparent xylene and thencemented with neutral gum For each slice six fields (under200x magnification) were selected Positive Masson stainingfor collagen depositionwas analyzed using by Image-Pro Plusmultimedia color pathological image analysis software Theratio of collagen deposition to the viewed area was calculatedand averaged

27 KGFandHMGB1Expression in LungTissue Keratinocytegrowth factor (KGF) antibody was purchased from Biorbyt(Cambridge UK) and the immunohistochemistry kit wasfrom Gene Technology (Shanghai China) High mobilitygroup box 1 protein (HMGB1) antibody was purchasedfrom Santa Cruz Biotechnology (Santa Cruz CA) andthe immunohistochemistry kit was from Gene Technology(Shanghai China) Lung tissue sections were deparaffinizedaccording to kit instructions and then stained with hema-toxylin and viewed with light microscopy Images wereanalyzed with Media Cybernetics Image-Pro Plus imageanalysis software Each slice was assessed using 6 fields ofintegrated optical density (IOD) which represented proteinexpression

28 Measurement of Inflammatory Mediators and sIgA byELISA The sacrificed mice were placed in a supine positionand perfused with two 075ml aliquots of ice-cold normalsaline (NS) Each animal was lavaged five times Lavage fluidwas collected and the cellular contents and bronchoalveolarlavage (BAL) fluid were separated by centrifugation Super-natant was used to measure secretory immunoglobulin A(sIgA) with enzyme-linked immunosorbent assay (ELISA)kits (Abbexa Cambridge UK) according to the manufac-turerrsquos instructions Optical density at 450 nm was measuredwith Microplate Reader 3 (MK3) (Lei Bo Shanghai China)

Lung tissue (01 g) was placed in a 15ml EP tube toprepare 10 lung homogenate Homogenate was centrifugedat 12000 rpm and 4∘C for 20min Supernatant used tomeasure inflammatory mediators from interleukin-4 (IL-4) interleukin-6 (IL-6) interleukin-10 (IL-10) interleukin-17 (IL-17) interleukin-1120573 (IL-1120573) and tumor necrosis factor(TNF-120572) with enzyme-linked immunosorbent assay (ELISA)kits (R amp D Minneapolis MN) according to the manufac-turerrsquos instructions Optical density at 450 nm was measuredwith Microplate Reader 3 (MK3) (Lei Bo Shanghai China)

29 Real-Time Reverse Transcriptase Polymerase Chain Reac-tion (RT-PCR) RT-PCR was used to measure IL-8 and IgAexpression in mouse lung tissues Total RNA was extractedfrom 100mg lung tissuewithTrizol after a one-step extraction

Table 1 PM25-related diseases identified through Polysearch

Number 119885 score Disease name1 9 Respiratory disease2 81 Asthma3 77 Lung cancer4 58 Cardiovascular disease5 37 COPD6 22 Atherosclerosis7 12 Ischemic stroke8 08 Pneumonia9 07 Gestational diabetes mellitus10 07 Pulmonary embolism

protocol cDNA was synthesized by reverse transcriptionwith 2120583g RNA 1 120583l oligo (dT) and DEPC water and 12 120583llung tissue 120573-Actin primer sequence is as follows forwardprimer 51015840-GTGACGTTGACATCCGTAAAGA-31015840 and thereverse primer 51015840-GTAACAGTCCGCCTAGAAGCAC-31015840IL-8 primer sequence is as follows forward primer 51015840-CATCTTCGTCCGTCCCTGTG-31015840 and reverse primer 51015840-GCCAACAGTAGCCTTCACCCA-31015840 IgA primer sequenceis as follows forward primer 51015840-GCTACAGTGTGTCCA-GCGTCCT-31015840 and reverse primer 51015840-TGCCAGACTCAG-GATGGGTAAC-31015840 Quantitative analysis was performedusing the 2minusΔΔCt method

3 Statistics

Data are represented as means plusmn standard deviation Sta-tistical analysis was conducted with SPSS 170 softwareComparisons among multiple groups were analyzed withone-way ANOVA with a Tukey-Kramer post hoc correctionSingle comparisons were made with an unpaired two-tailedStudentrsquos 119905-test Differences were considered statistically sig-nificant if 119901 lt 005

4 Results

41 PM25-Related Disease Prioritization and Predicted Tar-gets Polysearch platform analysis yielded a list of PM25related diseases (Table 1) which were prioritized based ona relevancy score and expressed as a 119885 score which refersto the number of standard deviations of the relevancy scoreabove the mean value A higher 119885 score denotes a lesserlikelihood that the outcome is due to chance Polysearchplatform queries confirmed that 98 10 and 9 target proteinswere associated with Astragalus radix paeoniae rubra andPsoralea corylifolia respectively (Figures 1ndash5)

42 Effect of BFHX on Mouse Pulmonary Function Com-pared with controls lung inspiratory and expiratory resis-tances were significantly greater (119901 lt 001 119901 lt 005)in PM25 mice Airway compliance and maximum forcedexpiratory flow were less in PM25 mice BFHX intervention


HMOXLTB4DH CA1 BALp38

TelomeraseSuccinate

dehydrogenase(protein family

or complex) TGFB1 VEGF

TIMP1

ornithinedecarboxylase

ioredoxin

PHT1

albumin

5lipoxygenase

acetylcholinereceptor

AMPK

AS160Radixpaeoniaerubra

MAPK

Bcl2

T bet

Superoxidedismutase

Notch1NFATc3

ATPase PI3KAT2

p65

complementC3

ATF6

P glycoprotein

BFGF

PARP

IL10

CXCL12

CATCYP3A4

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dependentkinases

(protein family or complex)

G-CSF

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TG2

Gracile

VCAM1 keap1

aFGFALDR

TyrosinaseTNFR1

A10

Sirtuin 1TRPA1

TSLPIL17 IL13ABPA

B7H3AdiponectinIgE

BDNFPeriostinBeta CateninVisfatin

Psoraleacorylifolia

Monoamineoxidases

CES1

Smoothmuscle actin

complex I CASP3 CYC

ERA

PTP1BCalcineurin


CD35PPARA CCL2

Protein kinase D1

CD45

PSAP CCR5CD11c

SERCA2 AGT JNK3CD8 CCL5IL8

SAPS

LDHMMP1IL2

Pyrophosphatase

PPARG Myostatin IFNgammaAstragalus

c Jun N terminalkinase

PendrinICAM1SulfatetransportersCaspase 3

N33IL4

MLCK

MicroRNA

IL6

LAMA

TNFA IVF

CD4

CD25

Statins Myosin

STAT1

STAT3

MMP2MMP9

MTL4MUC1

NPYIL1B

Calpain(protein family

or complex)

IL18

IL12

TLR4CAPE

IL15

MTHFR

CD69

ImmunoglobulinIL5

Interleukins

IL33 IL17F CC16ADAM33

HMGB1HASC

GATA3

GAP43

PBE

ORMDL3

CTLA4

Chitinase

5lipoxygenaseCD86

EGFR

Asthma

Interleukin 5

MicroRNAsChymase

proteinTyrosine

phosphatase

Figure 1 Potential targets of BFHX in asthma Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents asthma round blue nodes represent drug targets red nodes represent drug targets of disease

P53 MTHFR MicroRNAs

EML4EGFR

E cadherin

Lung cancer

CYP4502A6

p21 protein

Fascin

B7H1

PTEN

HER2

Beta catenin

KRAS

LUNX

MALAT1

MDM2 c Myc

GSTT1

CHRNA5

CHRNA3

GSTP1

CEACAM5

CDK2

HSP90AB1

CD133CXCR4

CYP1B1

CYP2E1

FBP1

GSTM1

IL10

Bcl2

MAPK

MMP9

STAT3

MMP2

TERT

STK11

SCLC

ROS1

RASSF1A

TRAF6

HMOX

Radixpaeoniaerubra

BALLTB4DH

CD35


or complex)

P glycoprotein

CD8

Chymase

CCR5

CD69

Cyclindependentkinases



AS160

Albumin

AMPK

ALDR

CD11c

IL18

Heparanase

Gracile

IL1B

G-CSF

MUC1

CD25

MTL4

CYP3A4

N33

JNK3

Astragalus

ICAM1

IL8

Myosin

Myostatin

keap1Interleukin 5

LDH

NFATc3

IL12

TIMP1

TelomeraseTG2

TGFB1

ioredoxin

IFNgamma

Notch1Ornithine

decarboxylase

IL15

PPARA

Superoxidedismutase

Proteintyrosine

phosphatase

PHT1

MicroRNAs

MMP1

ATF6ATPase

EC-NOS

IL2

BFGFPTP1B

Protein kinase D1

Succinatedehydrogenase(protein family

or complex)

Calcineurin(protein family

or complex)

PSAP

SAPS

Pyrophosphatase

SERCA2

IL6

CA1

CASP3

CXCL12

PI3K

CAPETyrosinase

PPARGp65CD4 Statins

STAT1Caspase 3

CD45 CATSulfatetransporters

VCAM1TNFR1

TNFATLR4

T betVEGF

ComplementC3

AGTAT2

CCL5A10

Acetylcholinereceptor

CCL2

5lipoxygenase

aFGF

complex I

Smoothmuscle actin

Psoraleacorylifolia

Monoamineoxidases CYCPARP ERACES1

p38 IL4

WISP1XRCC1

XRCC3ABCB1ALDH1ALK

API4

CLPTM1LVEGFR2 BRAFmiR21IL17

CK19VIMPIK3CA

BCRP

Figure 2 Potential targets of BFHX in lung cancer Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents lung cancer round blue nodes represent drug targets red nodes represent drug targets of disease

significantly decreased inspiratory (119901 lt 001) and expiratoryresistance (119901 lt 005) and increased dynamic lung complianceand maximum forced expiratory flow (119901 lt 001) in PM25mice Thus BFHX intervention significantly improved lungfunction and reduced airway resistance and increased airwaycompliance (Figure 6) in PM25 mice

43 Effect of BFHX on PM25-Induced Pulmonary Histopa-thology in Mice In the normal group and the BFHX groupbronchial mucosa and bronchial wall structures were intactand alveolar structural integrity was intact Some inflam-matory cells had infiltrated alveolar spaces but there waslittle interstitial inflammation and lung capillary structures

were intact with no bleeding Figure 7 shows that com-pared with the normal group and the BFHX group PM25exposure caused histological injury such as widened alveolarsepta capillary congestion and minor hemorrhages of smallairways BFHX treatment significantly reduced histologicalinjury and reduced congestion and hemorrhage of smallairways and recruitment

44 Effect of BFHX on Lung Collagen Deposition in MiceControls had collagen deposition in many small airways andfibrosis was noted around the vascular wall PM25-exposedlung tissues had thickened airways with obvious collagendeposition smaller alveoli with wider septa and obvious


NFE2L2

Interleukin

S100B

SERPINA1

SERPINE2

SFTP1

Paraoxonase

MMP20mtTFA

Neutrophilelastase

Acetylcholinereceptors HTR4

GATA3

IL13

MicroRNAsMMP12

LAMALeptin

GSTP1

GSTM1

CHRNA5

CHRNA3

Chemokines

CFTR

HMGB1OPG

Hemoglobin

GSTT1ElastinFOXP3

IL17

HHIP

HD2

IREB2

COPD

EGR1

CXCR2

CYP1A1

EGLN2

EGFR

Immunoglobulin

PDE4A

IL33

IL32

IL22

MMP9

TIMP1

MAPK

p38

IL8

IL1B

IL6

IL10

VEGF

PI3K

Ornithinedecarboxylase

IFNgamma

Tyrosinase

MMP2


AMPK

EC-NOS

CYP3A4

AT2MUC1Myosin

MyostatinN33


or complex) chymase

c Jun N terminalKinase

ATPase


or complex)

CD35

CD25

CD45BFGF

CD69

complementC3

AstragalusVCAM1


or complex)

CD11cATF6

G-CSF

IL18Heparanase

ICAM1IL12IL15IL2

Gracile

P glycoprotein

Notch1

Superoxidedismutase

NFATc3

PHT1

PTP1B

Pyrophosphatase

PSAP

protein kinase D1

5lipoxygenase

JNK3

PPARG

PPARA

Interleukin 5

SAPS

LDH

MicroRNAs

PTX3

SOCS3

TRAIL

ROR1SPD

RAGE

Surfactantprotein B

Sirtuin1

CD11b

CCSP

CTRP5

CTLA4

Cyclindependent

kinases(protein family

or complex) AS160

CCR5CCL5

CCL2CATCaspase 3

CA1CXCL12

BAL

IL4LTB4DH Bcl2

Sulfatetransporters

MTL4 keap1

STAT3

CAPE

Proteintyrosine

phosphatase

A10

p65

TGFB1ioredoxin

STAT1

TNFR1TLR4

ALDR

aFGFAGT

Albumin

MMP1

Smoothmuscle actin

PARP

CASP3ERA

CYC

Monoamineoxidases

complex I

CES1HMOX

CD8

TelomeraseCD4

SERCA2TNFA

T bet

TG2Statins

ADAM33IgEACHE

XRCC5

S100A4

Ubiquitin

CPAP

VDB

COX2

Adiponectin

BD1CRP

AQP5

CST3

BAFF

ADRB2 Radixpaeoniae

rubraPsoraleacorylifolia

Figure 3 Potential targets of BFHX in COPD Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents COPD round blue nodes represent drug targets red nodes represent drug targets of disease

GAP

AD7

gp91phox

ADAM33

GBP5

ADPRTADAM28

ADAM10

Gal3Phe3

TREM1

PAG1

UPA

PFGE

ACHEVWF

Ferritin

AD3

PIGN

ASCABPA

Fatty acid bindingprotein Transferrin

ZFP36L1

C10CA125

Chitinase 3 like 1 COPD6 Pneumonia

CPAP

BDNFHAP

HCAP Bradykinin

HELIOS AvianB99ARG1

FER

CD86

ChitinaseCFTR

CVID

CSF2CTLA3CTRL CMH7COLEC7CRP

CTSS

IMP 1ImportinIPS

ImmunoglobulinKidsK20

IRF5Interleukins

O13

NOD2NTMProgranulin Interferon

PPTOSM

IL25

PRSPPAI1

PLEKHA7 p42P2Y2Prothrombin

BALLTB4DHCA1

IL1B

HMOXCXCL12

TNFA


IL12

VEGF

IL8

CD4

STAT3

Statins

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Telomerase

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Succinatedehydrogenase

(proteinfamily or complex)

T bet Proteinkinase D1

ioredoxin

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SAPS

Superoxidedismutase

Sulfatetransporters

Cyclindependent

kinases(proteinfamily or complex)

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Pyrophosphatase

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PHT1

CD69p65


Chymase

PGlycoprotein

Notch1N33

LDH

TNFR1

IL18Interleukin 5

CD8

PSAP

CYP3A4

PI3K

PPARA

Myosin

EC-NOS

IL4

IL10AGT

IL6

TLR4

PSA

PTX3PSPC

REL

Q10RAGE

PSPB

SCT

SPIN

SCAP

SFTPA2

SOD

SCCA

SIGIRR

SARS

SAPS2

SCIN

Lipocalin 2

MAPK

MAC387

LEPR

MBL

MDP

ST2TFI

MLKL

Endoglin

Tie2

MincleETT

MRP8P97

MPO

rombomodulin

TPATR

TLR9

TLR1TLR2

TRAF6

DHPS

CXCL5

DHRS2

CXCL2

ELA2

CytolysinCYLD

EGFR

DHFR

RIP1

LAMP

LAMA

CXCL1

L12L selectin

RF

SAARIP3

Smoothmuscle

actinCYCComplex I

CASP3PARP

ERAMonoamineoxidases

CES1

ATF6c Jun N

terminalkinase

ComplementC3

AS160AT2

Calcineurin(proteinfamily or complex)BFGF

proteinTyrosine

phosphatase

Myostatin

MMP1CD45MMP2

MMP9

CD35

MTL4MUC1

ICAM1Caspase 3CAPE

Astragalus

ATPase

IFNgamma

TyrosinaseHeparanase

CAT

G-CSF

Gracile

CD11cCCR5

JNK3

CCL2

IL2CCL5

IL15

aFGF

VCAM1

ALDRAlbumin

Bcl2 MAPK

AMPK

5Lipoxygenase

A10

Keap1MicroRNAsCalpain


CD25

HFABP

Heparanase AnnexinsHemopexin Annexin A1

ANX2

CD44CD143

CBG

CABP

CD62

CCCKR4

CalciumChannel

CD64

AFP

AminopeptidaseALB

AHF

ANGPTL2Hemoglobin

HIES

Hla a

HGF

IFNG

ICS

HMGB1

HSPC008

IgE

Musashi1

IL22

ICOS

Neuraminidase

Plasminogen

IL16

Muscles

IL17IL1RA

IL13

HP

APA

HSP72

BNP32

HSP60

ATP12A

AQP4

APOB100

HLAHLADOA

Atg16L1

PsoraleacorylifoliaRadix

paeoniaerubra

DRB1lowast11

Figure 4 Potential targets of BFHX in pneumonia Blue triangle represents Astragalus radix paeoniae rubra and Psoralea corylifolia yellowdiamond represents pneumonia round blue nodes represent drug targets red nodes represent drug targets of disease

fibrosis Compared with PM25 lungs BFHX-treated tissuehad less tracheal and lung interstitial fibrosis (Figure 8)ThusBFHX significantly alleviated collagen deposition in PM25mice

45 Effect of BFHX on HMGB1 and KGF Expression inMouse Lung Tissues HMGB1 expression in alveolar tissue

was significantly greater in PM25 tissues compared withcontrols (119901 lt 001) and the BFHX intervention group (119901 lt001 Figures 9(a) and 9(c)) suggesting reduced inflammationwas due to BFHX Also in lung tissue of PM25-exposedanimals KGF expression in tracheal mucosa and alveolartissue was significantly greater than in normal mice and theBFHX intervention group (119901 lt 005 Figures 9(b) and 9(d))


HFABP

HMOX1Integrin

HaptoglobinHemoglobin

IFB BAL

IL10 p38

LTB4DH CA1HMOX

MAPK

CXCL12

IL4Bcl2

Pulmonary

embolism

cTnI

ASPS

CXCL4FGFR2

CRAT

CD309

ERA

PARPCYC

Complex I

CASP3

Monoamine

Smoothmuscle actin

CES1

VEGF

Albumin

Statins

IL6

CYP3A4

PSAP

BET1

ADM

APE

ANPB

ACPAArginase

FX

APC

CTPA

cTnT

Interferon

CRP

ARF

APS

ARG2

APOE

GPVI

CYP2C9

FDG

GGT

ADAMTS13

TIMP1

Proteintyrosine

phosphatase

Superoxidedismutase


or complex)

ioredoxin

TG2

BMPR2BNP

CD62

CD62E

PLJAMA

PAI1

Interleukins

Factor VIIa

MicroRNA134MMP20

MTHFR

SERPINC1

PVAPROS

SMARCAL1

Plasminogen

SCUBE1

PROC

NOS3

NPSA

PERC

Methemoglobin

Immunoglobulin

TPA

SERPINA1

SPARrombin

romboplastin

VKORC1

VV

PASP

Muscles

PATE

JAK2

KS1

TNFA

5lipoxygenase

PPARG

TNFR1Tyrosinase

PPARA

VCAM1

aFGF

Caspase 3MMP9

ATPase

IL8

Heparanase

Interleukin 5BFGF

Astragalus

IL2

PTP1B

ICAM1STAT1

SERCA2

MMP2PI3K

MMP1

G-CSF SAPS

Gracile



or complex)

AS160

AGT


or complex) ALDR


AMPK

A10

STAT3IL1B

ATF6

keap1T bet

ComplementC3

IL12

IL18CD45 AT2IL15

TelomeraseCCR5

MicroRNAs

CCL5

LDH


NFATc3

CD11c

Notch1

CD35

P glycoprotein

Myostatin

CD4

N33 CCL2

MUC1

Cyclindependent


or complex) JNK3MTL4

CATMyosin

CAPE

Sulfatetransporters

CD69

Chymase

CD8

PHT1

IFNgamma

EC-NOS

p65

CD25

Protein kinase D1

TLR4

TGFB1Pyrophosphatase

Radixpaeoniae

rubra

oxidases

Psoraleacorylifolia

Figure 5 Potential targets of BFHX in pulmonary embolism Blue triangle representsAstragalus radix paeoniae rubra and Psoralea corylifoliayellow diamond represents pulmonary embolism round blue nodes represent drug targets red nodes represent drug targets of disease

Normal Model BFHX00

05

10

15

RL-m

ean

(cm

H2Omiddots

m)

lowastlowast lowastlowast

(a)Normal Model BFHX

00

05

10

15

20

25

lowast lowast

RL-m

ean

(cm

H2Omiddots

m)

(b)

Normal Model BFHX000

002

004

006

Cdy

n-m

ean

(mlc

mH

2O

)

lowastlowast

lowastlowast

(c)Normal Model BFHX

0

1

2

3

PEF

(mls

)

lowast lowastlowast

(d)

Figure 6 Effect of BFHX onmouse pulmonary function Compared with PM25-exposedmice themean of lung inspiratory (a) and expiratoryresistance (b) decreased significantly after BFHX intervention Dynamic lung compliance (c) and peak expiratory flow rate (d) significantlyimproved Inhale and exhale resistance airway compliance and peak expiratory flow data are means plusmn SD lowast119901 lt 005 and lowastlowast119901 lt 001compared with the PM25 exposure group 119899 ge 8


Normal (200x) BFHX (200x) Model (200x)

(a)


(b)

Figure 7 Effect of BFHX on PM25-induced pulmonary histopathology in mice Pulmonary tissue of trachea and pulmonary interstitialinflammatory infiltration in PM25 model mice and BFHX groups Inflammatory infiltration with BFHX was less compared with the PM25exposure group (a) 200x and (b) 400x

46 Effect of BFHX on Inflammatory Mediator Expression inMouse Lung Tissues Compared with normal groups IL-4IL-6 IL-10 IL-1120573 IL-17 and TNF-120572was greater in lung tissueof PM25modelmice andBFHXgroups After treatmentwithBFHX cytokines were reduced compared with model groups(Figure 10)

47 Effect of BFHX on IL-8 IgA and sIgA Expression acrossTreatment Groups Control lung tissue homogenates had lessIL-8 and IgA mRNA than those measured in PM25-exposedmouse tissue (119901 lt 001 for both) sIgA expression in the BALfluid is less than thatmeasured in PM25-exposedmouse BALfluid (119901 lt 001 for both) BFHX treatment reduced IL-8 IgAand sIgA significantly (119901 lt 001 for both) compared withmouse from the PM25 exposure group (Figure 11)

5 Discussion

Leveraging bioinformatics and computer science networkpharmacology offers an effective approach to studying drugand disease interactions by constructing a ldquomolecular-target-diseaserdquo relationship [17] Using a network pharmacologyplatform we confirmed that PM25 exposure contributed torespiratory and heart disease The respiratory system wasinitially injured but the circulatory and neural systems couldbe subsequently involved via multipathological pathways

Data show that BFHX targets many genes related to PM25respiratory diseases such as asthma lung cancer COPDpneumonia and pulmonary embolism in complicated anddiverse ways BFHX regulates expression of inflammatoryfactors (TNF-120572 IL-1120573 IL-4 IL-6 and IL-10) and immuneregulation (CD4+ and CD8+ cells) and may be involved inadjusting related signaling pathways (BCL2 STAT3 and P38)in regulating cell proliferation chemotaxis and apoptosis(Figures 1ndash5)

Different sized particles can damage different parts ofthe respiratory system Fine particulate matter (1ndash25 120583mdiameter PM1ndash25) can enter bronchi and the deeper res-piratory tract Those of 01ndash1120583m diameter (PM01ndash1) candeeply penetrate the lung and ultrafine particles (PM01)can penetrate alveoli and enter the circulation [25] PM25can reduce lung function and induce asthma episodesbronchitis lung cancer and other respiratory diseases [26]Animal models of lung injury can be established by nasallyinstilling PM25 suspensions and in mice this manifests aslung tissue and small airway damage as well as alveolarand pulmonary interstitial inflammation BFHX repairedairway damage and improved lung function in these modelsand decreased airway resistance and increased lung com-pliance Data show that BFHX can improve lung functionreducing PM25-induced lung injury and promoting heal-ing BFHX also significantly reduced collagen deposition



(a)

Normal Model BFHX0

10

20

30

Mas

son

(per

area

)


(b)

Figure 8 Effect of BFHX on lung collagen deposition in mice (a) Light microscopy (200x) Blue represents collagen fibers and mucus redrepresents cartilage cytoplasm muscle cellulose and glia and dark blue represents nuclei (b) Percent of fibrotic lung tissue in the entirefield lowastlowast119901 lt 001 compared with tissue from the PM25 exposure group 119899 = 9

which may improve fibrosis and improve lung function(Figure 6)

TNF-120572 and IL-1120573 are important proinflammatorycytokines that activate and recruit inflammatory cellsenhance inflammatory response [27 28] and stimulateproliferative response of smooth muscle cells and fibroblastin the airway resulting in remodeling [29 30] IL-4 is agrowth factor secreted by T cells and IL-6 produced byresponses of mononuclear macrophages endothelial cellsfibroblasts and other cells to IL-1 and TNF-120572 [31ndash33]contributes to immune defenses and can enhance airwayinflammation IL-10 is an immunomodulatory cytokine andis made mainly by activated monocytes lymphocytes andepithelial cells A high level of IL-10 was produced afterdamage [34 35] and IL-8 was significantly increased in localinflammation serum and body fluid because of infectionand some autoimmune diseases [36 37] BFHX significantlydecreased TNF-120572 IL-1120573 IL-6 IL-10 IL-4 and IL-8 in lungof PM25 mode mice (Figures 10 and 11)

HMGB1 is widely distributed in the lymph brain liverlung heart kidney and other tissues Under stimulation ofIL-1 and TNF-120572 HMGB1 can be secreted into the extra-cellular space to promote cytokine production and extend

inflammation [38] Recent studies indicate that activationof HMGB1 signaling is associated with acute lung injuryasthma pulmonary fibrosis and other respiratory diseasesand HMGB1 expression is correlated with respiratory diseaseseverity [39] BFHX alleviated inflammation and decreasedsubsequent injury to lung tissue of PM25 model mice(Figure 9)

KGF is a cytokine synthesized by 120574120575T cells and stimulatesepithelial cell proliferation differentiation andmigration andpromotes mucosal repair maintenance of mucosal integrityKGF stimulates synthesis storage and secretion of pul-monary surfactant in type II alveolar epithelial cells (AECII) reduces alveolar surface gas-liquid surface tension andprevents excessive expiratory alveolar collapse and over-inspiratory expansion to maintain alveolar shape KGF secre-tion is increased promoting tissue repair but KGF is reportedto be associated with early growth of mesothelial cellsafter asbestos exposure which contributes to lung fibrosis[40] IL-17 a powerful proinflammatory factor is a majorcytokines synthesized by 120574120575Tcells and reflects their biologicalactivity to a certain extent [41] 120574120575T cells are importantduring the transition from innate immune cells to acquiredimmune cells So BFHX may control 120574120575T cell activity to



(a)


(b)

Normal Model BFHX0

10000

20000

30000

HM

GB1

IOD

lowastlowastlowastlowast


0

10000

20000

30000

40000

KGF

IOD

lowast lowast

(d)

Figure 9 Effect of BFHX on HMGB1 and KGF expression in PM25 mouse lung tissues (a) HMGB1 expression in alveolar tissues wassignificantly greater in PM25 tissues compared with controls and the BFHX intervention group (200x) (b) KGF expression in trachealmucosa and alveolar tissues was significantly greater than in normal mice (200x) (c) HMGB1 expression quantified (d) KGF expressionquantified Values are means plusmn SD lowast119901 lt 005 119899 = 9

reduce lung injury of in PM25 model mice and reduceexpression of KGF to reduce PM25-induced lung fibrosis(Figures 9 and 10)

sIgA is a human IgA exocrine antibody found in themucosa of respiratory gastrointestinal and urogenital tractsand is a first line of defense against bacterial and viraladsorption and colonization on epithelial cell surfaces [6]Respiratory tract infections pathogenic microbial invasionand adhesion to the epithelium stimulate a local mucosalimmune response by increasing synthesis and secretionof sIgA Data show that in PM25 mice BFHX reducedsIgA secretion and reduced airway damage suggesting that

BFHXameliorated localmucosal inflammation (Figure 11) Insummary our data suggest that BFHX reduced pathologicalresponses induced by PM25 via regulation of inflammatorymediators in mouse lungs

6 Conclusion

We noted that PM25 could stimulate lung tissue inflamma-tory factors promote generation of secretory immunoglob-ulin and KGF and cause collagen fiber deposition in lungtissue BFHXmodified the respiratory tract mucosal immuneresponse and inhibited secretion of immunoglobulin to


Normal Model BFHX0

5000

10000

15000

20000

25000

TNF-

훼(p

gm

l)


Normal Model BFHX0

2000

4000

6000

8000

IL-1훽

(pg

ml)

lowastlowast lowast

Normal Model BFHX0

500

1000

1500IL

-17

(pg

ml)

lowast lowast

Normal Model BFHX0

2000

4000

6000

8000

IL-1

0 (p

gm

l)

lowastlowast lowast

0

2000

4000

6000

8000

10000

IL-6

(pg

ml)

Normal Model BFHX

lowastlowast lowast

0

100

200

300

400

500

IL-4

(pg

ml)

Normal Model BFHX

lowastlowastlowast

Figure 10 Effect of BFHX on expression of inflammatory mediators BFHX-treatedmice had less inflammation than untreated PM25-exposedmice IL-4 IL-6 IL-10 IL-17 1L-1120573 andTNF-120572 expression inmice (meansplusmn SD) lowast119901 lt 005 and lowastlowast119901 lt 001 comparedwith the PM25 exposuregroup 119899 ge 6

Normal Model BFHX0

1

2

3

IL-8


Normal Model BFHX00

01

02

03

04

05

IgA


Normal Model BFHX0

20

40

60

80

sIgA

BA

L (n

gm

l)


Figure 11 IL-8 IgA and sIgA expression in different mouse groups Control lung tissue homogenates had less IL-8 and IgA mRNA thanPM25-exposed mouse tissue sIgA expression in BAL fluid is less than PM25-exposed mouse BAL fluid lowastlowast119901 lt 001 119899 ge 7

reduce release of inflammatory cytokines and collagen fiberdeposition It also improved lung function and alleviatedinjury in a PM25 mouse model

Competing Interests

All authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contributions

Yue Jing Hongchun Zhang Zhe Cai and Yukun Zhaocontributed equally to this work Ye Wu Xuan Zheng Ying

Liu Yuying Qin Mingjie Gu and Jin Jin also contributedequally to this work

References

[1] Q Zhao K-B He Y-L Ma et al ldquoRegional PM pollution inBeijing and surrounding area during summertimerdquo Huan JingKe Xue vol 30 no 7 pp 1873ndash1880 2009

[2] J G Watson ldquoVisibility science and Regulationrdquo Journal of theAir and Waste Management Association vol 52 no 6 pp 628ndash713 2002

[3] S Wang and J Hao ldquoAir quality management in China issueschallenges and optionsrdquo Journal of Environmental Sciences vol24 no 1 pp 2ndash13 2012


[4] Z Mu J Zhao N Xu L Yao Y Li and J Meng ldquoVerticaland temporal variation of PM10 in Yanta District Xirsquoan duringwinterrdquo Acta Scientiae Circumstantiae vol 31 no 7 pp 1509ndash1516 2011

[5] C A Pope III R T Burnett M J Thun et al ldquoLung cancercardiopulmonary mortality and long-term exposure to fineparticulate air pollutionrdquo The Journal of the American MedicalAssociation vol 287 no 9 pp 1132ndash1141 2002

[6] Y Ma R Chen G Pan et al ldquoFine particulate air pollutionand daily mortality in Shenyang Chinardquo Science of the TotalEnvironment vol 409 no 13 pp 2473ndash2477 2011

[7] N Li X Peng B Zhang W Yin and S Yu ldquoA time-seriesstudy between air pollutant and the respiratory daily mortalityin Guangzhourdquo Journal of Huazhong University of Science andTechnology Health Sciences vol 3 no 6 pp 863ndash867 2010

[8] Y Guo A G Barnett Y Zhang S TongW Yu andX Pan ldquoTheshort-term effect of air pollution on cardiovascular mortality inTianjin China comparison of time series and case-crossoveranalysesrdquo Science of the Total Environment vol 409 no 2 pp300ndash306 2010

[9] Y-S Zhang M-G Zhou Y-P Jia et al ldquoTime-series analysisof association between inhalable particulate matter and dailymortality amongurban residents inTianjinrdquoZhonghua LiuXingBing Xue Za Zhi vol 31 no 5 pp 544ndash548 2010

[10] H Orru E Teinemaa T Lai et al ldquoHealth impact assessment ofparticulate pollution in Tallinn using fine spatial resolution andmodeling techniquesrdquo Environmental Health A Global AccessScience Source vol 8 no 1 article no 7 2009

[11] Y-J Ren X-Y Li M-J Jin K Chen H-Q Xiang and Q-M Liu ldquoCase-crossover studies of air particulate matter pol-lution and cardiovascular disease deathrdquo China EnvironmentalScience vol 27 no 5 pp 657ndash660 2007

[12] J Zhang H Meng G Zhang Z Zhang W Zhao and XPan ldquoRelationship between air pollution and daily respiratorysystem disease mortality in Chaoyang District Beijing a time-series analysisrdquo Journal of Environmental andHealth vol 28 no9 pp 788ndash791 2011

[13] K-Y Hsin S Ghosh and H Kitano ldquoCombining machinelearning systems and multiple docking simulation packages toimprove docking prediction reliability for network pharmacol-ogyrdquo PLoS ONE vol 8 no 12 Article ID e83922 2013

[14] W Tao X Xu X Wang et al ldquoNetwork pharmacology-basedprediction of the active ingredients and potential targets ofChinese herbal Radix Curcumae formula for application tocardiovascular diseaserdquo Journal of Ethnopharmacology vol 145no 1 pp 1ndash10 2013

[15] Y Wang X Gao B Zhang and Y Cheng ldquoBuilding method-ology for discovering and developing Chinese medicine basedon network biologyrdquo Zhongguo Zhong Yao Za Zhi vol 36 no 2pp 228ndash231 2011

[16] F J Prado-Prado E Uriarte F Borges and H Gonzalez-Dıaz ldquoMulti-target spectral moments for QSAR and complexnetworks study of antibacterial drugsrdquo European Journal ofMedicinal Chemistry vol 44 no 11 pp 4516ndash4521 2009

[17] A S Azmi and R M Mohammad ldquoRectifying cancer drugdiscovery through network pharmacologyrdquo Future MedicinalChemistry vol 6 no 5 pp 529ndash539 2014

[18] B-F Cheng Y-Y HouM Jiang Z-Y Zhao L-Y Dong and GBai ldquoAnti-inflammatory mechanism of Qingfei Xiaoyan Wanstudied with network pharmacologyrdquo Yaoxue Xuebao vol 48no 5 pp 686ndash693 2013

[19] D Wu Z Xie and P Di ldquoClinical effect of BuFeiHuoXuecapsulesrdquo China Practical Medicine vol 7 no 8 pp 148ndash1492012

[20] B Li and L Su ldquoClinical observation of BuFeiHuoXue capsuleseffect on lung ventilationrdquo Practical Journal of Cardiac CerebralPneumal and Vascular Disease vol 14 no 9 pp 728ndash729 2006

[21] L Tian G Cao andG Liu ldquoEffect of BuFeiHuoXue capsules onpneumosilicosisrdquo Guangdong Yi Xue vol 35 no 11 pp 1778ndash1779 2014

[22] Y Wu L Yang X Zheng et al ldquoCharacterization and sourceapportionment of particulate PAHs in the roadside environ-ment in Beijingrdquo Science of the Total Environment vol 470-471pp 76ndash83 2014

[23] Y Qin Y Jing Y Liu et al ldquoInfluence of Guben ZhikeGranules on lung function and morphology of lung injurymouse model induced by PM25rdquo China Journal of TraditionalChinese Medicine and Pharmacy vol 31 no 3 pp 1028ndash10312016

[24] Z-H Jiang and W-M Song ldquoEffects of NF-120581B in acute lunginjury induced by PM25 inmicerdquo Journal of Environmental andOccupational Medicine vol 22 no 6 pp 483ndash501 2005

[25] H Yang X Zou H Wang and Y Liu ldquoStudy progress onPM25 in atmospheric environmentrdquo Journal of Meteorologyand Environment vol 28 no 3 pp 77ndash82 2012

[26] X Yang L Feng and P Wei ldquoAtmospherical PM25 and itsharmnessrdquo Frontier Science vol 6 no 21 pp 22ndash30 2012

[27] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[28] W J Ming L Bersani and A Mantovani ldquoTumor necrosisfactor is chemotactic for monocytes and polymorphonuclearleukocytesrdquo Journal of Immunology vol 138 no 5 pp 1469ndash1474 1987

[29] R Ma J Chen Z Y Li J C Tang Y F Wang and X JCai ldquoDecorin accelerates the liver regeneration after partialhepatectomy in fibrotic micerdquo Chinese Medical Journal vol 127no 14 pp 2679ndash2685 2014

[30] A S Bossa VM C Salemi S P Ribeiro et al ldquoPlasma cytokineprofile in tropical endomyocardial fibrosis predominance ofTNF-a IL-4 and IL-10rdquo PLoS ONE vol 9 no 10 Article IDe108984 2014

[31] C-Y Lin H Zhang K-C Cheng and A S Slutsky ldquoMechani-cal ventilationmay increase susceptibility to the development ofbacteremiardquoCritical CareMedicine vol 31 no 5 pp 1429ndash14342003

[32] S A Jones P J Richards J Scheller and S Rose-John ldquoIL-6transsignaling the in vivo consequencesrdquo Journal of Interferonand Cytokine Research vol 25 no 5 pp 241ndash253 2005

[33] A L Mora E Torres-Gonzalez M Rojas et al ldquoActiva-tion of alveolar macrophages via the alternative pathway inherpesvirus-induced lung fibrosisrdquo American Journal of Respi-ratory Cell and Molecular Biology vol 35 no 4 pp 466ndash4732006

[34] E R Kabyemela A Muehlenbachs M Fried J D Kurtis TK Mutabingwa and P E Duffy ldquoMaternal peripheral bloodlevel of IL-10 as a marker for inflammatory placental malariardquoMalaria Journal vol 7 article 26 2008

[35] J Liu S Huang X-Z Su J Song and F Lu ldquoBlockage ofGalectin-receptor interactions by 120572-lactose exacerbates plas-modium berghei-induced pulmonary immunopathologyrdquo Sci-entific Reports vol 6 Article ID 32024 2016


[36] I A J Giebelen D J Van Westerloo G J LaRosa A F DeVos and T Van Der Poll ldquoLocal stimulation of 1205727 cholinergicreceptors inhibits LPS-induced TNF-120572 release in the mouselungrdquo Shock vol 28 no 6 pp 700ndash703 2007

[37] S Nakayama H Mukae H Ishii et al ldquoComparison of BALFconcentrations of ENA-78 and IP10 in patients with idiopathicpulmonary fibrosis and nonspecific interstitial pneumoniardquoRespiratory Medicine vol 99 no 9 pp 1145ndash1151 2005

[38] W Huang Y Tang and L Li ldquoHMGB1 a potent proinflamma-tory cytokine in sepsisrdquoCytokine vol 51 no 2 pp 119ndash126 2010

[39] S GangemiMCasciaro G Trapani et al ldquoAssociation betweenHMGB1 and COPD a systematic reviewrdquo Mediators of Inflam-mation vol 2015 Article ID 164913 8 pages 2015

[40] I Y Adamson ldquoEarly mesothelial cell proliferation afterasbestos exposure in vivo and in vitro studiesrdquo EnvironmentalHealth Perspectives vol 105 supplement 5 pp 1205ndash1208 1997

[41] G Zhang K F Zhou and Z H Lu ldquoInterleukin-17 enhancesthe removal of respiratory syncytial virus in mice by promotingneutrophil migration and reducing interferon-gamma expres-sionrdquo Genetics and Molecular Research vol 15 no 1 2016

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


diseases and cancer [5ndash12] and these problems represent asignificant social and economic burden

Based on systems biology and pharmacology networkpharmacology leverages network analysis and screens nodesto identify proteins critical to a disease for drug design[13 14] Network pharmacology can be used to investigatesynergism of multicomponent drugs to identify high efficacyand low toxicity agents with multiple targets [15 16] Chineseherbal formulas often have numerous targets and are com-prised of many substances so network pharmacologymay beuseful for studying traditional Chinese medicine [17 18]

Bufei Huoxue (BFHX) capsules contain three commonChinese herbal products Astragalus radix paeoniae rubraand Psoralea corylifolia and have been approved by the ChinaFood and Drug Administration (Number Z20030063) forthe treatment of pulmonary heart disease Clinical studiessuggest that these compounds improve pulmonary ventila-tion function and reduce silicosis and lung inflammation[19ndash21] Thus we studied BFHX capsules and PM25-relatedrespiratory disease using a network pharmacology platformThe effects of BFHX capsules on PM25-induced pulmonaryinflammation were evaluated and the underlying mecha-nisms of action were investigated in mice

2 Materials and Methods

21 PM25-Related Diseases PM25-related diseases wereidentified using Polysearch System (httpwishartbiologyualbertacapolysearchindexhtm) a web-based text-min-ing system for extracting relationships among human dis-eases genes drugs and metabolism PM25-related dis-eases were searched and extracted statements were manuallyscreened According to 119885-values the top 10 diseases wereselected for further study

22 Prediction of Disease Pathways and BFHX Targets Alltarget genes or proteins for each BFHX component (Astra-galus radix paeoniae rubra and Psoralea corylifolia) wereobtained using Polysearch and diseases were selected frompredictions based on keywords Targets were networked andvisualized using Cytoscape 321 software Drug- and disease-related targets were merged using Merge to screen key targetproteins

23 PM25 Mouse Model and Drug Intervention

231 PM25 Sampling and Suspension Preparation PM25samples were collected from three sites in Beijing in thesummer and winter seasons of 2011 and 2012 The three siteswere a roadside site located 2m from the curb of the North4th Ring Road an urban site on the campus of Tsinghua Uni-versity and a rural site situated in the countryside of MiyunSampling was conducted by Anderson particulate samplerHBL-GUV (Thermo Fisher Waltham MA) equipped witha PTFE membrane for two consecutive weeks [22] At theend of sample collection the PTFE membrane carryingPM25 was cut into 1 times 3 cm pieces and placed in ultrapurewater Particles were eluted three times under ultrasonic

oscillation 40min each Liquid containing the particulatematter was filtered through six layers of sterile gauze andcentrifuged at 12000 rpm at 4∘C for 30min The lower layerof the suspension was collected and vacuum-freeze dried toyield PM25 particles which were then stored at minus20∘C Tomake a stock solution PM25 particles were weighed andsuspended in saline at the desired concentrations after beingultrasonicated for 15min and sterilized Samples were storedat 4∘C Detailedmethods can be found in related papers by usand other authors [23 24]

232 Drugs BFHX capsules were provided by Lei Yun ShangPharmaceutical Limited (Suzhou Jiangsu China) The drypowder was taken from the capsules and suspended indistilled water The mixture was stored at 4∘C

233 Animals Adult female ICR mice (Beijing HFKBiotechnology Co Ltd China 22ndash26 g) were housed inseparate cages with food and water freely available understandard laboratory conditions of 22ndash28∘C and relativehumidity of 50ndash60 with a 12 h light12 h dark cycle Animaltreatment and maintenance were performed in accordancewith requirements of and the study protocol was approvedby the institutional animal care and use committee at theChina-Japan Friendship Hospital in Beijing (Permit 150202) All efforts were made to minimize suffering

Sixty ICR female mice were randomized into 3 groupsnormal controls PM25 exposure and BFHX interventiongroups (119873 = 20group) Controls were given an intranasalinstillation of saline (20120583lmouse) on days 1 8 15 and 22ThePM25 exposure group was given an intranasal instillation ofPM25 suspension (40mgkg 20 120583lmouse) on days 1 8 15and 22 and each received oral saline (02mlmouseday) fromdays 1 to 22 The BFHX intervention group was treated aswas the PM25 exposure group except that BFHX (082 gkg02mlmouseday) instead of saline was given daily Animalswere sacrificed 48 h after the last treatment

24 Lung Function Mice were anesthetized with 2 pento-barbital (04ml40 g ip) and secured in a supine position tobe orotracheally intubated Then mice were transferred toa plethysmography platform and lung function analysis wasmeasured lung include inspiratory resistance (RL) expira-tory resistance (RE) dynamic lung compliance (Cdyn) andpeak expiratory flow (PEF) using an AniRes2005 apparatus(Beilanbo Science and Technology Co Ltd Beijing China)

25 Lung Histology Mice were sacrificed and subjected tothoracotomy with lung resectionThe left lung lobe was fixedin 10 formalin for 24 h and then dehydrated embeddedin paraffin and sectioned Sections were stained with hema-toxylin and eosin (HampE) according to the routine stainingmethod and observed under an optical microscopeThe rightlung lobe was homogenized for molecular studies

26 Masson Staining Lung collagen content was quantifiedwith Masson trichrome staining Paraffin sections were firstdewaxed followed by washing with tap and then distilled










3 Statistics


4 Results





TelomeraseSuccinate



TIMP1


ioredoxin

PHT1

albumin

5lipoxygenase


AMPK


MAPK

Bcl2

T bet

Superoxidedismutase

Notch1NFATc3

ATPase PI3KAT2

p65

complementC3

ATF6

P glycoprotein

BFGF

PARP

IL10

CXCL12

CATCYP3A4

EC-NOSCyclin

dependentkinases


G-CSF

Heparanase

TG2

Gracile

VCAM1 keap1

aFGFALDR

TyrosinaseTNFR1

A10

Sirtuin 1TRPA1

TSLPIL17 IL13ABPA

B7H3AdiponectinIgE


Psoraleacorylifolia

Monoamineoxidases

CES1

Smoothmuscle actin

complex I CASP3 CYC

ERA

PTP1BCalcineurin


CD35PPARA CCL2

Protein kinase D1

CD45

PSAP CCR5CD11c


SAPS

LDHMMP1IL2

Pyrophosphatase




N33IL4

MLCK

MicroRNA

IL6

LAMA

TNFA IVF

CD4

CD25

Statins Myosin

STAT1

STAT3

MMP2MMP9

MTL4MUC1

NPYIL1B


or complex)

IL18

IL12

TLR4CAPE

IL15

MTHFR

CD69

ImmunoglobulinIL5

Interleukins


HMGB1HASC

GATA3

GAP43

PBE

ORMDL3

CTLA4

Chitinase

5lipoxygenaseCD86

EGFR

Asthma

Interleukin 5

MicroRNAsChymase

proteinTyrosine

phosphatase


P53 MTHFR MicroRNAs

EML4EGFR

E cadherin

Lung cancer

CYP4502A6

p21 protein

Fascin

B7H1

PTEN

HER2

Beta catenin

KRAS

LUNX

MALAT1

MDM2 c Myc

GSTT1

CHRNA5

CHRNA3

GSTP1

CEACAM5

CDK2

HSP90AB1

CD133CXCR4

CYP1B1

CYP2E1

FBP1

GSTM1

IL10

Bcl2

MAPK

MMP9

STAT3

MMP2

TERT

STK11

SCLC

ROS1

RASSF1A

TRAF6

HMOX

Radixpaeoniaerubra

BALLTB4DH

CD35


or complex)

P glycoprotein

CD8

Chymase

CCR5

CD69




AS160

Albumin

AMPK

ALDR

CD11c

IL18

Heparanase

Gracile

IL1B

G-CSF

MUC1

CD25

MTL4

CYP3A4

N33

JNK3

Astragalus

ICAM1

IL8

Myosin

Myostatin

keap1Interleukin 5

LDH

NFATc3

IL12

TIMP1

TelomeraseTG2

TGFB1

ioredoxin

IFNgamma

Notch1Ornithine

decarboxylase

IL15

PPARA

Superoxidedismutase

Proteintyrosine

phosphatase

PHT1

MicroRNAs

MMP1

ATF6ATPase

EC-NOS

IL2

BFGFPTP1B

Protein kinase D1


or complex)


or complex)

PSAP

SAPS

Pyrophosphatase

SERCA2

IL6

CA1

CASP3

CXCL12

PI3K

CAPETyrosinase

PPARGp65CD4 Statins

STAT1Caspase 3


VCAM1TNFR1

TNFATLR4

T betVEGF

ComplementC3

AGTAT2

CCL5A10


CCL2

5lipoxygenase

aFGF

complex I

Smoothmuscle actin

Psoraleacorylifolia


p38 IL4

WISP1XRCC1

XRCC3ABCB1ALDH1ALK

API4


CK19VIMPIK3CA

BCRP







NFE2L2

Interleukin

S100B

SERPINA1

SERPINE2

SFTP1

Paraoxonase

MMP20mtTFA

Neutrophilelastase


GATA3

IL13

MicroRNAsMMP12

LAMALeptin

GSTP1

GSTM1

CHRNA5

CHRNA3

Chemokines

CFTR

HMGB1OPG

Hemoglobin

GSTT1ElastinFOXP3

IL17

HHIP

HD2

IREB2

COPD

EGR1

CXCR2

CYP1A1

EGLN2

EGFR

Immunoglobulin

PDE4A

IL33

IL32

IL22

MMP9

TIMP1

MAPK

p38

IL8

IL1B

IL6

IL10

VEGF

PI3K


IFNgamma

Tyrosinase

MMP2


AMPK

EC-NOS

CYP3A4

AT2MUC1Myosin

MyostatinN33


or complex) chymase


ATPase


or complex)

CD35

CD25

CD45BFGF

CD69

complementC3

AstragalusVCAM1


or complex)

CD11cATF6

G-CSF

IL18Heparanase

ICAM1IL12IL15IL2

Gracile

P glycoprotein

Notch1

Superoxidedismutase

NFATc3

PHT1

PTP1B

Pyrophosphatase

PSAP

protein kinase D1

5lipoxygenase

JNK3

PPARG

PPARA

Interleukin 5

SAPS

LDH

MicroRNAs

PTX3

SOCS3

TRAIL

ROR1SPD

RAGE

Surfactantprotein B

Sirtuin1

CD11b

CCSP

CTRP5

CTLA4

Cyclindependent


or complex) AS160

CCR5CCL5

CCL2CATCaspase 3

CA1CXCL12

BAL

IL4LTB4DH Bcl2

Sulfatetransporters

MTL4 keap1

STAT3

CAPE

Proteintyrosine

phosphatase

A10

p65

TGFB1ioredoxin

STAT1

TNFR1TLR4

ALDR

aFGFAGT

Albumin

MMP1

Smoothmuscle actin

PARP

CASP3ERA

CYC

Monoamineoxidases

complex I

CES1HMOX

CD8

TelomeraseCD4

SERCA2TNFA

T bet

TG2Statins

ADAM33IgEACHE

XRCC5

S100A4

Ubiquitin

CPAP

VDB

COX2

Adiponectin

BD1CRP

AQP5

CST3

BAFF

ADRB2 Radixpaeoniae



GAP

AD7

gp91phox

ADAM33

GBP5

ADPRTADAM28

ADAM10

Gal3Phe3

TREM1

PAG1

UPA

PFGE

ACHEVWF

Ferritin

AD3

PIGN

ASCABPA


ZFP36L1

C10CA125


CPAP

BDNFHAP

HCAP Bradykinin

HELIOS AvianB99ARG1

FER

CD86

ChitinaseCFTR

CVID


CTSS

IMP 1ImportinIPS


IRF5Interleukins

O13


PPTOSM

IL25

PRSPPAI1


BALLTB4DHCA1

IL1B

HMOXCXCL12

TNFA


IL12

VEGF

IL8

CD4

STAT3

Statins

TGFB1

Telomerase

PPARG




ioredoxin

p38

TIMP1

PTP1BTG2

SERCA2

SAPS

Superoxidedismutase

Sulfatetransporters

Cyclindependent


STAT1

Pyrophosphatase

NFATc3

PHT1

CD69p65


Chymase

PGlycoprotein

Notch1N33

LDH

TNFR1

IL18Interleukin 5

CD8

PSAP

CYP3A4

PI3K

PPARA

Myosin

EC-NOS

IL4

IL10AGT

IL6

TLR4

PSA

PTX3PSPC

REL

Q10RAGE

PSPB

SCT

SPIN

SCAP

SFTPA2

SOD

SCCA

SIGIRR

SARS

SAPS2

SCIN

Lipocalin 2

MAPK

MAC387

LEPR

MBL

MDP

ST2TFI

MLKL

Endoglin

Tie2

MincleETT

MRP8P97

MPO

rombomodulin

TPATR

TLR9

TLR1TLR2

TRAF6

DHPS

CXCL5

DHRS2

CXCL2

ELA2

CytolysinCYLD

EGFR

DHFR

RIP1

LAMP

LAMA

CXCL1

L12L selectin

RF

SAARIP3

Smoothmuscle

actinCYCComplex I

CASP3PARP


CES1

ATF6c Jun N

terminalkinase

ComplementC3

AS160AT2


proteinTyrosine

phosphatase

Myostatin

MMP1CD45MMP2

MMP9

CD35

MTL4MUC1

ICAM1Caspase 3CAPE

Astragalus

ATPase

IFNgamma


CAT

G-CSF

Gracile

CD11cCCR5

JNK3

CCL2

IL2CCL5

IL15

aFGF

VCAM1

ALDRAlbumin

Bcl2 MAPK

AMPK

5Lipoxygenase

A10



CD25

HFABP


ANX2

CD44CD143

CBG

CABP

CD62

CCCKR4

CalciumChannel

CD64

AFP

AminopeptidaseALB

AHF

ANGPTL2Hemoglobin

HIES

Hla a

HGF

IFNG

ICS

HMGB1

HSPC008

IgE

Musashi1

IL22

ICOS

Neuraminidase

Plasminogen

IL16

Muscles

IL17IL1RA

IL13

HP

APA

HSP72

BNP32

HSP60

ATP12A

AQP4

APOB100

HLAHLADOA

Atg16L1


paeoniaerubra

DRB1lowast11






HFABP

HMOX1Integrin


IFB BAL

IL10 p38

LTB4DH CA1HMOX

MAPK

CXCL12

IL4Bcl2

Pulmonary

embolism

cTnI

ASPS

CXCL4FGFR2

CRAT

CD309

ERA

PARPCYC

Complex I

CASP3

Monoamine

Smoothmuscle actin

CES1

VEGF

Albumin

Statins

IL6

CYP3A4

PSAP

BET1

ADM

APE

ANPB

ACPAArginase

FX

APC

CTPA

cTnT

Interferon

CRP

ARF

APS

ARG2

APOE

GPVI

CYP2C9

FDG

GGT

ADAMTS13

TIMP1

Proteintyrosine

phosphatase

Superoxidedismutase


or complex)

ioredoxin

TG2

BMPR2BNP

CD62

CD62E

PLJAMA

PAI1

Interleukins

Factor VIIa

MicroRNA134MMP20

MTHFR

SERPINC1

PVAPROS

SMARCAL1

Plasminogen

SCUBE1

PROC

NOS3

NPSA

PERC

Methemoglobin

Immunoglobulin

TPA

SERPINA1

SPARrombin

romboplastin

VKORC1

VV

PASP

Muscles

PATE

JAK2

KS1

TNFA

5lipoxygenase

PPARG

TNFR1Tyrosinase

PPARA

VCAM1

aFGF

Caspase 3MMP9

ATPase

IL8

Heparanase

Interleukin 5BFGF

Astragalus

IL2

PTP1B

ICAM1STAT1

SERCA2

MMP2PI3K

MMP1

G-CSF SAPS

Gracile



or complex)

AS160

AGT


or complex) ALDR


AMPK

A10

STAT3IL1B

ATF6

keap1T bet

ComplementC3

IL12

IL18CD45 AT2IL15

TelomeraseCCR5

MicroRNAs

CCL5

LDH


NFATc3

CD11c

Notch1

CD35

P glycoprotein

Myostatin

CD4

N33 CCL2

MUC1

Cyclindependent



CATMyosin

CAPE

Sulfatetransporters

CD69

Chymase

CD8

PHT1

IFNgamma

EC-NOS

p65

CD25

Protein kinase D1

TLR4


Radixpaeoniae

rubra

oxidases

Psoraleacorylifolia


Normal Model BFHX00

05

10

15

RL-m

ean

(cm

H2Omiddots

m)



00

05

10

15

20

25

lowast lowast

RL-m

ean

(cm

H2Omiddots

m)

(b)


002

004

006

Cdy

n-m

ean

(mlc

mH

2O

)

lowastlowast

lowastlowast


0

1

2

3

PEF

(mls

)

lowast lowastlowast

(d)




(a)


(b)




5 Discussion






(a)

Normal Model BFHX0

10

20

30

Mas

son

(per

area

)


(b)









(a)


(b)

Normal Model BFHX0

10000

20000

30000

HM

GB1

IOD



0

10000

20000

30000

40000

KGF

IOD

lowast lowast

(d)





6 Conclusion



Normal Model BFHX0

5000

10000

15000

20000

25000

TNF-

훼(p

gm

l)


Normal Model BFHX0

2000

4000

6000

8000

IL-1훽

(pg

ml)

lowastlowast lowast

Normal Model BFHX0

500

1000

1500IL

-17

(pg

ml)

lowast lowast

Normal Model BFHX0

2000

4000

6000

8000

IL-1

0 (p

gm

l)

lowastlowast lowast

0

2000

4000

6000

8000

10000

IL-6

(pg

ml)

Normal Model BFHX

lowastlowast lowast

0

100

200

300

400

500

IL-4

(pg

ml)

Normal Model BFHX

lowastlowastlowast


Normal Model BFHX0

1

2

3

IL-8


Normal Model BFHX00

01

02

03

04

05

IgA


Normal Model BFHX0

20

40

60

80

sIgA

BA

L (n

gm

l)




Competing Interests





References

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























3 Statistics


4 Results





TelomeraseSuccinate



TIMP1


ioredoxin

PHT1

albumin

5lipoxygenase


AMPK


MAPK

Bcl2

T bet

Superoxidedismutase

Notch1NFATc3

ATPase PI3KAT2

p65

complementC3

ATF6

P glycoprotein

BFGF

PARP

IL10

CXCL12

CATCYP3A4

EC-NOSCyclin

dependentkinases


G-CSF

Heparanase

TG2

Gracile

VCAM1 keap1

aFGFALDR

TyrosinaseTNFR1

A10

Sirtuin 1TRPA1

TSLPIL17 IL13ABPA

B7H3AdiponectinIgE


Psoraleacorylifolia

Monoamineoxidases

CES1

Smoothmuscle actin

complex I CASP3 CYC

ERA

PTP1BCalcineurin


CD35PPARA CCL2

Protein kinase D1

CD45

PSAP CCR5CD11c


SAPS

LDHMMP1IL2

Pyrophosphatase




N33IL4

MLCK

MicroRNA

IL6

LAMA

TNFA IVF

CD4

CD25

Statins Myosin

STAT1

STAT3

MMP2MMP9

MTL4MUC1

NPYIL1B


or complex)

IL18

IL12

TLR4CAPE

IL15

MTHFR

CD69

ImmunoglobulinIL5

Interleukins


HMGB1HASC

GATA3

GAP43

PBE

ORMDL3

CTLA4

Chitinase

5lipoxygenaseCD86

EGFR

Asthma

Interleukin 5

MicroRNAsChymase

proteinTyrosine

phosphatase


P53 MTHFR MicroRNAs

EML4EGFR

E cadherin

Lung cancer

CYP4502A6

p21 protein

Fascin

B7H1

PTEN

HER2

Beta catenin

KRAS

LUNX

MALAT1

MDM2 c Myc

GSTT1

CHRNA5

CHRNA3

GSTP1

CEACAM5

CDK2

HSP90AB1

CD133CXCR4

CYP1B1

CYP2E1

FBP1

GSTM1

IL10

Bcl2

MAPK

MMP9

STAT3

MMP2

TERT

STK11

SCLC

ROS1

RASSF1A

TRAF6

HMOX

Radixpaeoniaerubra

BALLTB4DH

CD35


or complex)

P glycoprotein

CD8

Chymase

CCR5

CD69




AS160

Albumin

AMPK

ALDR

CD11c

IL18

Heparanase

Gracile

IL1B

G-CSF

MUC1

CD25

MTL4

CYP3A4

N33

JNK3

Astragalus

ICAM1

IL8

Myosin

Myostatin

keap1Interleukin 5

LDH

NFATc3

IL12

TIMP1

TelomeraseTG2

TGFB1

ioredoxin

IFNgamma

Notch1Ornithine

decarboxylase

IL15

PPARA

Superoxidedismutase

Proteintyrosine

phosphatase

PHT1

MicroRNAs

MMP1

ATF6ATPase

EC-NOS

IL2

BFGFPTP1B

Protein kinase D1


or complex)


or complex)

PSAP

SAPS

Pyrophosphatase

SERCA2

IL6

CA1

CASP3

CXCL12

PI3K

CAPETyrosinase

PPARGp65CD4 Statins

STAT1Caspase 3


VCAM1TNFR1

TNFATLR4

T betVEGF

ComplementC3

AGTAT2

CCL5A10


CCL2

5lipoxygenase

aFGF

complex I

Smoothmuscle actin

Psoraleacorylifolia


p38 IL4

WISP1XRCC1

XRCC3ABCB1ALDH1ALK

API4


CK19VIMPIK3CA

BCRP







NFE2L2

Interleukin

S100B

SERPINA1

SERPINE2

SFTP1

Paraoxonase

MMP20mtTFA

Neutrophilelastase


GATA3

IL13

MicroRNAsMMP12

LAMALeptin

GSTP1

GSTM1

CHRNA5

CHRNA3

Chemokines

CFTR

HMGB1OPG

Hemoglobin

GSTT1ElastinFOXP3

IL17

HHIP

HD2

IREB2

COPD

EGR1

CXCR2

CYP1A1

EGLN2

EGFR

Immunoglobulin

PDE4A

IL33

IL32

IL22

MMP9

TIMP1

MAPK

p38

IL8

IL1B

IL6

IL10

VEGF

PI3K


IFNgamma

Tyrosinase

MMP2


AMPK

EC-NOS

CYP3A4

AT2MUC1Myosin

MyostatinN33


or complex) chymase


ATPase


or complex)

CD35

CD25

CD45BFGF

CD69

complementC3

AstragalusVCAM1


or complex)

CD11cATF6

G-CSF

IL18Heparanase

ICAM1IL12IL15IL2

Gracile

P glycoprotein

Notch1

Superoxidedismutase

NFATc3

PHT1

PTP1B

Pyrophosphatase

PSAP

protein kinase D1

5lipoxygenase

JNK3

PPARG

PPARA

Interleukin 5

SAPS

LDH

MicroRNAs

PTX3

SOCS3

TRAIL

ROR1SPD

RAGE

Surfactantprotein B

Sirtuin1

CD11b

CCSP

CTRP5

CTLA4

Cyclindependent


or complex) AS160

CCR5CCL5

CCL2CATCaspase 3

CA1CXCL12

BAL

IL4LTB4DH Bcl2

Sulfatetransporters

MTL4 keap1

STAT3

CAPE

Proteintyrosine

phosphatase

A10

p65

TGFB1ioredoxin

STAT1

TNFR1TLR4

ALDR

aFGFAGT

Albumin

MMP1

Smoothmuscle actin

PARP

CASP3ERA

CYC

Monoamineoxidases

complex I

CES1HMOX

CD8

TelomeraseCD4

SERCA2TNFA

T bet

TG2Statins

ADAM33IgEACHE

XRCC5

S100A4

Ubiquitin

CPAP

VDB

COX2

Adiponectin

BD1CRP

AQP5

CST3

BAFF

ADRB2 Radixpaeoniae



GAP

AD7

gp91phox

ADAM33

GBP5

ADPRTADAM28

ADAM10

Gal3Phe3

TREM1

PAG1

UPA

PFGE

ACHEVWF

Ferritin

AD3

PIGN

ASCABPA


ZFP36L1

C10CA125


CPAP

BDNFHAP

HCAP Bradykinin

HELIOS AvianB99ARG1

FER

CD86

ChitinaseCFTR

CVID


CTSS

IMP 1ImportinIPS


IRF5Interleukins

O13


PPTOSM

IL25

PRSPPAI1


BALLTB4DHCA1

IL1B

HMOXCXCL12

TNFA


IL12

VEGF

IL8

CD4

STAT3

Statins

TGFB1

Telomerase

PPARG




ioredoxin

p38

TIMP1

PTP1BTG2

SERCA2

SAPS

Superoxidedismutase

Sulfatetransporters

Cyclindependent


STAT1

Pyrophosphatase

NFATc3

PHT1

CD69p65


Chymase

PGlycoprotein

Notch1N33

LDH

TNFR1

IL18Interleukin 5

CD8

PSAP

CYP3A4

PI3K

PPARA

Myosin

EC-NOS

IL4

IL10AGT

IL6

TLR4

PSA

PTX3PSPC

REL

Q10RAGE

PSPB

SCT

SPIN

SCAP

SFTPA2

SOD

SCCA

SIGIRR

SARS

SAPS2

SCIN

Lipocalin 2

MAPK

MAC387

LEPR

MBL

MDP

ST2TFI

MLKL

Endoglin

Tie2

MincleETT

MRP8P97

MPO

rombomodulin

TPATR

TLR9

TLR1TLR2

TRAF6

DHPS

CXCL5

DHRS2

CXCL2

ELA2

CytolysinCYLD

EGFR

DHFR

RIP1

LAMP

LAMA

CXCL1

L12L selectin

RF

SAARIP3

Smoothmuscle

actinCYCComplex I

CASP3PARP


CES1

ATF6c Jun N

terminalkinase

ComplementC3

AS160AT2


proteinTyrosine

phosphatase

Myostatin

MMP1CD45MMP2

MMP9

CD35

MTL4MUC1

ICAM1Caspase 3CAPE

Astragalus

ATPase

IFNgamma


CAT

G-CSF

Gracile

CD11cCCR5

JNK3

CCL2

IL2CCL5

IL15

aFGF

VCAM1

ALDRAlbumin

Bcl2 MAPK

AMPK

5Lipoxygenase

A10



CD25

HFABP


ANX2

CD44CD143

CBG

CABP

CD62

CCCKR4

CalciumChannel

CD64

AFP

AminopeptidaseALB

AHF

ANGPTL2Hemoglobin

HIES

Hla a

HGF

IFNG

ICS

HMGB1

HSPC008

IgE

Musashi1

IL22

ICOS

Neuraminidase

Plasminogen

IL16

Muscles

IL17IL1RA

IL13

HP

APA

HSP72

BNP32

HSP60

ATP12A

AQP4

APOB100

HLAHLADOA

Atg16L1


paeoniaerubra

DRB1lowast11






HFABP

HMOX1Integrin


IFB BAL

IL10 p38

LTB4DH CA1HMOX

MAPK

CXCL12

IL4Bcl2

Pulmonary

embolism

cTnI

ASPS

CXCL4FGFR2

CRAT

CD309

ERA

PARPCYC

Complex I

CASP3

Monoamine

Smoothmuscle actin

CES1

VEGF

Albumin

Statins

IL6

CYP3A4

PSAP

BET1

ADM

APE

ANPB

ACPAArginase

FX

APC

CTPA

cTnT

Interferon

CRP

ARF

APS

ARG2

APOE

GPVI

CYP2C9

FDG

GGT

ADAMTS13

TIMP1

Proteintyrosine

phosphatase

Superoxidedismutase


or complex)

ioredoxin

TG2

BMPR2BNP

CD62

CD62E

PLJAMA

PAI1

Interleukins

Factor VIIa

MicroRNA134MMP20

MTHFR

SERPINC1

PVAPROS

SMARCAL1

Plasminogen

SCUBE1

PROC

NOS3

NPSA

PERC

Methemoglobin

Immunoglobulin

TPA

SERPINA1

SPARrombin

romboplastin

VKORC1

VV

PASP

Muscles

PATE

JAK2

KS1

TNFA

5lipoxygenase

PPARG

TNFR1Tyrosinase

PPARA

VCAM1

aFGF

Caspase 3MMP9

ATPase

IL8

Heparanase

Interleukin 5BFGF

Astragalus

IL2

PTP1B

ICAM1STAT1

SERCA2

MMP2PI3K

MMP1

G-CSF SAPS

Gracile



or complex)

AS160

AGT


or complex) ALDR


AMPK

A10

STAT3IL1B

ATF6

keap1T bet

ComplementC3

IL12

IL18CD45 AT2IL15

TelomeraseCCR5

MicroRNAs

CCL5

LDH


NFATc3

CD11c

Notch1

CD35

P glycoprotein

Myostatin

CD4

N33 CCL2

MUC1

Cyclindependent



CATMyosin

CAPE

Sulfatetransporters

CD69

Chymase

CD8

PHT1

IFNgamma

EC-NOS

p65

CD25

Protein kinase D1

TLR4


Radixpaeoniae

rubra

oxidases

Psoraleacorylifolia


Normal Model BFHX00

05

10

15

RL-m

ean

(cm

H2Omiddots

m)



00

05

10

15

20

25

lowast lowast

RL-m

ean

(cm

H2Omiddots

m)

(b)


002

004

006

Cdy

n-m

ean

(mlc

mH

2O

)

lowastlowast

lowastlowast


0

1

2

3

PEF

(mls

)

lowast lowastlowast

(d)




(a)


(b)




5 Discussion






(a)

Normal Model BFHX0

10

20

30

Mas

son

(per

area

)


(b)









(a)


(b)

Normal Model BFHX0

10000

20000

30000

HM

GB1

IOD



0

10000

20000

30000

40000

KGF

IOD

lowast lowast

(d)





6 Conclusion



Normal Model BFHX0

5000

10000

15000

20000

25000

TNF-

훼(p

gm

l)


Normal Model BFHX0

2000

4000

6000

8000

IL-1훽

(pg

ml)

lowastlowast lowast

Normal Model BFHX0

500

1000

1500IL

-17

(pg

ml)

lowast lowast

Normal Model BFHX0

2000

4000

6000

8000

IL-1

0 (p

gm

l)

lowastlowast lowast

0

2000

4000

6000

8000

10000

IL-6

(pg

ml)

Normal Model BFHX

lowastlowast lowast

0

100

200

300

400

500

IL-4

(pg

ml)

Normal Model BFHX

lowastlowastlowast


Normal Model BFHX0

1

2

3

IL-8


Normal Model BFHX00

01

02

03

04

05

IgA


Normal Model BFHX0

20

40

60

80

sIgA

BA

L (n

gm

l)




Competing Interests





References

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















TelomeraseSuccinate



TIMP1


ioredoxin

PHT1

albumin

5lipoxygenase


AMPK


MAPK

Bcl2

T bet

Superoxidedismutase

Notch1NFATc3

ATPase PI3KAT2

p65

complementC3

ATF6

P glycoprotein

BFGF

PARP

IL10

CXCL12

CATCYP3A4

EC-NOSCyclin

dependentkinases


G-CSF

Heparanase

TG2

Gracile

VCAM1 keap1

aFGFALDR

TyrosinaseTNFR1

A10

Sirtuin 1TRPA1

TSLPIL17 IL13ABPA

B7H3AdiponectinIgE


Psoraleacorylifolia

Monoamineoxidases

CES1

Smoothmuscle actin

complex I CASP3 CYC

ERA

PTP1BCalcineurin


CD35PPARA CCL2

Protein kinase D1

CD45

PSAP CCR5CD11c


SAPS

LDHMMP1IL2

Pyrophosphatase




N33IL4

MLCK

MicroRNA

IL6

LAMA

TNFA IVF

CD4

CD25

Statins Myosin

STAT1

STAT3

MMP2MMP9

MTL4MUC1

NPYIL1B


or complex)

IL18

IL12

TLR4CAPE

IL15

MTHFR

CD69

ImmunoglobulinIL5

Interleukins


HMGB1HASC

GATA3

GAP43

PBE

ORMDL3

CTLA4

Chitinase

5lipoxygenaseCD86

EGFR

Asthma

Interleukin 5

MicroRNAsChymase

proteinTyrosine

phosphatase


P53 MTHFR MicroRNAs

EML4EGFR

E cadherin

Lung cancer

CYP4502A6

p21 protein

Fascin

B7H1

PTEN

HER2

Beta catenin

KRAS

LUNX

MALAT1

MDM2 c Myc

GSTT1

CHRNA5

CHRNA3

GSTP1

CEACAM5

CDK2

HSP90AB1

CD133CXCR4

CYP1B1

CYP2E1

FBP1

GSTM1

IL10

Bcl2

MAPK

MMP9

STAT3

MMP2

TERT

STK11

SCLC

ROS1

RASSF1A

TRAF6

HMOX

Radixpaeoniaerubra

BALLTB4DH

CD35


or complex)

P glycoprotein

CD8

Chymase

CCR5

CD69




AS160

Albumin

AMPK

ALDR

CD11c

IL18

Heparanase

Gracile

IL1B

G-CSF

MUC1

CD25

MTL4

CYP3A4

N33

JNK3

Astragalus

ICAM1

IL8

Myosin

Myostatin

keap1Interleukin 5

LDH

NFATc3

IL12

TIMP1

TelomeraseTG2

TGFB1

ioredoxin

IFNgamma

Notch1Ornithine

decarboxylase

IL15

PPARA

Superoxidedismutase

Proteintyrosine

phosphatase

PHT1

MicroRNAs

MMP1

ATF6ATPase

EC-NOS

IL2

BFGFPTP1B

Protein kinase D1


or complex)


or complex)

PSAP

SAPS

Pyrophosphatase

SERCA2

IL6

CA1

CASP3

CXCL12

PI3K

CAPETyrosinase

PPARGp65CD4 Statins

STAT1Caspase 3


VCAM1TNFR1

TNFATLR4

T betVEGF

ComplementC3

AGTAT2

CCL5A10


CCL2

5lipoxygenase

aFGF

complex I

Smoothmuscle actin

Psoraleacorylifolia


p38 IL4

WISP1XRCC1

XRCC3ABCB1ALDH1ALK

API4


CK19VIMPIK3CA

BCRP







NFE2L2

Interleukin

S100B

SERPINA1

SERPINE2

SFTP1

Paraoxonase

MMP20mtTFA

Neutrophilelastase


GATA3

IL13

MicroRNAsMMP12

LAMALeptin

GSTP1

GSTM1

CHRNA5

CHRNA3

Chemokines

CFTR

HMGB1OPG

Hemoglobin

GSTT1ElastinFOXP3

IL17

HHIP

HD2

IREB2

COPD

EGR1

CXCR2

CYP1A1

EGLN2

EGFR

Immunoglobulin

PDE4A

IL33

IL32

IL22

MMP9

TIMP1

MAPK

p38

IL8

IL1B

IL6

IL10

VEGF

PI3K


IFNgamma

Tyrosinase

MMP2


AMPK

EC-NOS

CYP3A4

AT2MUC1Myosin

MyostatinN33


or complex) chymase


ATPase


or complex)

CD35

CD25

CD45BFGF

CD69

complementC3

AstragalusVCAM1


or complex)

CD11cATF6

G-CSF

IL18Heparanase

ICAM1IL12IL15IL2

Gracile

P glycoprotein

Notch1

Superoxidedismutase

NFATc3

PHT1

PTP1B

Pyrophosphatase

PSAP

protein kinase D1

5lipoxygenase

JNK3

PPARG

PPARA

Interleukin 5

SAPS

LDH

MicroRNAs

PTX3

SOCS3

TRAIL

ROR1SPD

RAGE

Surfactantprotein B

Sirtuin1

CD11b

CCSP

CTRP5

CTLA4

Cyclindependent


or complex) AS160

CCR5CCL5

CCL2CATCaspase 3

CA1CXCL12

BAL

IL4LTB4DH Bcl2

Sulfatetransporters

MTL4 keap1

STAT3

CAPE

Proteintyrosine

phosphatase

A10

p65

TGFB1ioredoxin

STAT1

TNFR1TLR4

ALDR

aFGFAGT

Albumin

MMP1

Smoothmuscle actin

PARP

CASP3ERA

CYC

Monoamineoxidases

complex I

CES1HMOX

CD8

TelomeraseCD4

SERCA2TNFA

T bet

TG2Statins

ADAM33IgEACHE

XRCC5

S100A4

Ubiquitin

CPAP

VDB

COX2

Adiponectin

BD1CRP

AQP5

CST3

BAFF

ADRB2 Radixpaeoniae



GAP

AD7

gp91phox

ADAM33

GBP5

ADPRTADAM28

ADAM10

Gal3Phe3

TREM1

PAG1

UPA

PFGE

ACHEVWF

Ferritin

AD3

PIGN

ASCABPA


ZFP36L1

C10CA125


CPAP

BDNFHAP

HCAP Bradykinin

HELIOS AvianB99ARG1

FER

CD86

ChitinaseCFTR

CVID


CTSS

IMP 1ImportinIPS


IRF5Interleukins

O13


PPTOSM

IL25

PRSPPAI1


BALLTB4DHCA1

IL1B

HMOXCXCL12

TNFA


IL12

VEGF

IL8

CD4

STAT3

Statins

TGFB1

Telomerase

PPARG




ioredoxin

p38

TIMP1

PTP1BTG2

SERCA2

SAPS

Superoxidedismutase

Sulfatetransporters

Cyclindependent


STAT1

Pyrophosphatase

NFATc3

PHT1

CD69p65


Chymase

PGlycoprotein

Notch1N33

LDH

TNFR1

IL18Interleukin 5

CD8

PSAP

CYP3A4

PI3K

PPARA

Myosin

EC-NOS

IL4

IL10AGT

IL6

TLR4

PSA

PTX3PSPC

REL

Q10RAGE

PSPB

SCT

SPIN

SCAP

SFTPA2

SOD

SCCA

SIGIRR

SARS

SAPS2

SCIN

Lipocalin 2

MAPK

MAC387

LEPR

MBL

MDP

ST2TFI

MLKL

Endoglin

Tie2

MincleETT

MRP8P97

MPO

rombomodulin

TPATR

TLR9

TLR1TLR2

TRAF6

DHPS

CXCL5

DHRS2

CXCL2

ELA2

CytolysinCYLD

EGFR

DHFR

RIP1

LAMP

LAMA

CXCL1

L12L selectin

RF

SAARIP3

Smoothmuscle

actinCYCComplex I

CASP3PARP


CES1

ATF6c Jun N

terminalkinase

ComplementC3

AS160AT2


proteinTyrosine

phosphatase

Myostatin

MMP1CD45MMP2

MMP9

CD35

MTL4MUC1

ICAM1Caspase 3CAPE

Astragalus

ATPase

IFNgamma


CAT

G-CSF

Gracile

CD11cCCR5

JNK3

CCL2

IL2CCL5

IL15

aFGF

VCAM1

ALDRAlbumin

Bcl2 MAPK

AMPK

5Lipoxygenase

A10



CD25

HFABP


ANX2

CD44CD143

CBG

CABP

CD62

CCCKR4

CalciumChannel

CD64

AFP

AminopeptidaseALB

AHF

ANGPTL2Hemoglobin

HIES

Hla a

HGF

IFNG

ICS

HMGB1

HSPC008

IgE

Musashi1

IL22

ICOS

Neuraminidase

Plasminogen

IL16

Muscles

IL17IL1RA

IL13

HP

APA

HSP72

BNP32

HSP60

ATP12A

AQP4

APOB100

HLAHLADOA

Atg16L1


paeoniaerubra

DRB1lowast11






HFABP

HMOX1Integrin


IFB BAL

IL10 p38

LTB4DH CA1HMOX

MAPK

CXCL12

IL4Bcl2

Pulmonary

embolism

cTnI

ASPS

CXCL4FGFR2

CRAT

CD309

ERA

PARPCYC

Complex I

CASP3

Monoamine

Smoothmuscle actin

CES1

VEGF

Albumin

Statins

IL6

CYP3A4

PSAP

BET1

ADM

APE

ANPB

ACPAArginase

FX

APC

CTPA

cTnT

Interferon

CRP

ARF

APS

ARG2

APOE

GPVI

CYP2C9

FDG

GGT

ADAMTS13

TIMP1

Proteintyrosine

phosphatase

Superoxidedismutase


or complex)

ioredoxin

TG2

BMPR2BNP

CD62

CD62E

PLJAMA

PAI1

Interleukins

Factor VIIa

MicroRNA134MMP20

MTHFR

SERPINC1

PVAPROS

SMARCAL1

Plasminogen

SCUBE1

PROC

NOS3

NPSA

PERC

Methemoglobin

Immunoglobulin

TPA

SERPINA1

SPARrombin

romboplastin

VKORC1

VV

PASP

Muscles

PATE

JAK2

KS1

TNFA

5lipoxygenase

PPARG

TNFR1Tyrosinase

PPARA

VCAM1

aFGF

Caspase 3MMP9

ATPase

IL8

Heparanase

Interleukin 5BFGF

Astragalus

IL2

PTP1B

ICAM1STAT1

SERCA2

MMP2PI3K

MMP1

G-CSF SAPS

Gracile



or complex)

AS160

AGT


or complex) ALDR


AMPK

A10

STAT3IL1B

ATF6

keap1T bet

ComplementC3

IL12

IL18CD45 AT2IL15

TelomeraseCCR5

MicroRNAs

CCL5

LDH


NFATc3

CD11c

Notch1

CD35

P glycoprotein

Myostatin

CD4

N33 CCL2

MUC1

Cyclindependent



CATMyosin

CAPE

Sulfatetransporters

CD69

Chymase

CD8

PHT1

IFNgamma

EC-NOS

p65

CD25

Protein kinase D1

TLR4


Radixpaeoniae

rubra

oxidases

Psoraleacorylifolia


Normal Model BFHX00

05

10

15

RL-m

ean

(cm

H2Omiddots

m)



00

05

10

15

20

25

lowast lowast

RL-m

ean

(cm

H2Omiddots

m)

(b)


002

004

006

Cdy

n-m

ean

(mlc

mH

2O

)

lowastlowast

lowastlowast


0

1

2

3

PEF

(mls

)

lowast lowastlowast

(d)




(a)


(b)




5 Discussion






(a)

Normal Model BFHX0

10

20

30

Mas

son

(per

area

)


(b)









(a)


(b)

Normal Model BFHX0

10000

20000

30000

HM

GB1

IOD



0

10000

20000

30000

40000

KGF

IOD

lowast lowast

(d)





6 Conclusion



Normal Model BFHX0

5000

10000

15000

20000

25000

TNF-

훼(p

gm

l)


Normal Model BFHX0

2000

4000

6000

8000

IL-1훽

(pg

ml)

lowastlowast lowast

Normal Model BFHX0

500

1000

1500IL

-17

(pg

ml)

lowast lowast

Normal Model BFHX0

2000

4000

6000

8000

IL-1

0 (p

gm

l)

lowastlowast lowast

0

2000

4000

6000

8000

10000

IL-6

(pg

ml)

Normal Model BFHX

lowastlowast lowast

0

100

200

300

400

500

IL-4

(pg

ml)

Normal Model BFHX

lowastlowastlowast


Normal Model BFHX0

1

2

3

IL-8


Normal Model BFHX00

01

02

03

04

05

IgA


Normal Model BFHX0

20

40

60

80

sIgA

BA

L (n

gm

l)




Competing Interests





References

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















NFE2L2

Interleukin

S100B

SERPINA1

SERPINE2

SFTP1

Paraoxonase

MMP20mtTFA

Neutrophilelastase


GATA3

IL13

MicroRNAsMMP12

LAMALeptin

GSTP1

GSTM1

CHRNA5

CHRNA3

Chemokines

CFTR

HMGB1OPG

Hemoglobin

GSTT1ElastinFOXP3

IL17

HHIP

HD2

IREB2

COPD

EGR1

CXCR2

CYP1A1

EGLN2

EGFR

Immunoglobulin

PDE4A

IL33

IL32

IL22

MMP9

TIMP1

MAPK

p38

IL8

IL1B

IL6

IL10

VEGF

PI3K


IFNgamma

Tyrosinase

MMP2


AMPK

EC-NOS

CYP3A4

AT2MUC1Myosin

MyostatinN33


or complex) chymase


ATPase


or complex)

CD35

CD25

CD45BFGF

CD69

complementC3

AstragalusVCAM1


or complex)

CD11cATF6

G-CSF

IL18Heparanase

ICAM1IL12IL15IL2

Gracile

P glycoprotein

Notch1

Superoxidedismutase

NFATc3

PHT1

PTP1B

Pyrophosphatase

PSAP

protein kinase D1

5lipoxygenase

JNK3

PPARG

PPARA

Interleukin 5

SAPS

LDH

MicroRNAs

PTX3

SOCS3

TRAIL

ROR1SPD

RAGE

Surfactantprotein B

Sirtuin1

CD11b

CCSP

CTRP5

CTLA4

Cyclindependent


or complex) AS160

CCR5CCL5

CCL2CATCaspase 3

CA1CXCL12

BAL

IL4LTB4DH Bcl2

Sulfatetransporters

MTL4 keap1

STAT3

CAPE

Proteintyrosine

phosphatase

A10

p65

TGFB1ioredoxin

STAT1

TNFR1TLR4

ALDR

aFGFAGT

Albumin

MMP1

Smoothmuscle actin

PARP

CASP3ERA

CYC

Monoamineoxidases

complex I

CES1HMOX

CD8

TelomeraseCD4

SERCA2TNFA

T bet

TG2Statins

ADAM33IgEACHE

XRCC5

S100A4

Ubiquitin

CPAP

VDB

COX2

Adiponectin

BD1CRP

AQP5

CST3

BAFF

ADRB2 Radixpaeoniae



GAP

AD7

gp91phox

ADAM33

GBP5

ADPRTADAM28

ADAM10

Gal3Phe3

TREM1

PAG1

UPA

PFGE

ACHEVWF

Ferritin

AD3

PIGN

ASCABPA


ZFP36L1

C10CA125


CPAP

BDNFHAP

HCAP Bradykinin

HELIOS AvianB99ARG1

FER

CD86

ChitinaseCFTR

CVID


CTSS

IMP 1ImportinIPS


IRF5Interleukins

O13


PPTOSM

IL25

PRSPPAI1


BALLTB4DHCA1

IL1B

HMOXCXCL12

TNFA


IL12

VEGF

IL8

CD4

STAT3

Statins

TGFB1

Telomerase

PPARG




ioredoxin

p38

TIMP1

PTP1BTG2

SERCA2

SAPS

Superoxidedismutase

Sulfatetransporters

Cyclindependent


STAT1

Pyrophosphatase

NFATc3

PHT1

CD69p65


Chymase

PGlycoprotein

Notch1N33

LDH

TNFR1

IL18Interleukin 5

CD8

PSAP

CYP3A4

PI3K

PPARA

Myosin

EC-NOS

IL4

IL10AGT

IL6

TLR4

PSA

PTX3PSPC

REL

Q10RAGE

PSPB

SCT

SPIN

SCAP

SFTPA2

SOD

SCCA

SIGIRR

SARS

SAPS2

SCIN

Lipocalin 2

MAPK

MAC387

LEPR

MBL

MDP

ST2TFI

MLKL

Endoglin

Tie2

MincleETT

MRP8P97

MPO

rombomodulin

TPATR

TLR9

TLR1TLR2

TRAF6

DHPS

CXCL5

DHRS2

CXCL2

ELA2

CytolysinCYLD

EGFR

DHFR

RIP1

LAMP

LAMA

CXCL1

L12L selectin

RF

SAARIP3

Smoothmuscle

actinCYCComplex I

CASP3PARP


CES1

ATF6c Jun N

terminalkinase

ComplementC3

AS160AT2


proteinTyrosine

phosphatase

Myostatin

MMP1CD45MMP2

MMP9

CD35

MTL4MUC1

ICAM1Caspase 3CAPE

Astragalus

ATPase

IFNgamma


CAT

G-CSF

Gracile

CD11cCCR5

JNK3

CCL2

IL2CCL5

IL15

aFGF

VCAM1

ALDRAlbumin

Bcl2 MAPK

AMPK

5Lipoxygenase

A10



CD25

HFABP


ANX2

CD44CD143

CBG

CABP

CD62

CCCKR4

CalciumChannel

CD64

AFP

AminopeptidaseALB

AHF

ANGPTL2Hemoglobin

HIES

Hla a

HGF

IFNG

ICS

HMGB1

HSPC008

IgE

Musashi1

IL22

ICOS

Neuraminidase

Plasminogen

IL16

Muscles

IL17IL1RA

IL13

HP

APA

HSP72

BNP32

HSP60

ATP12A

AQP4

APOB100

HLAHLADOA

Atg16L1


paeoniaerubra

DRB1lowast11






HFABP

HMOX1Integrin


IFB BAL

IL10 p38

LTB4DH CA1HMOX

MAPK

CXCL12

IL4Bcl2

Pulmonary

embolism

cTnI

ASPS

CXCL4FGFR2

CRAT

CD309

ERA

PARPCYC

Complex I

CASP3

Monoamine

Smoothmuscle actin

CES1

VEGF

Albumin

Statins

IL6

CYP3A4

PSAP

BET1

ADM

APE

ANPB

ACPAArginase

FX

APC

CTPA

cTnT

Interferon

CRP

ARF

APS

ARG2

APOE

GPVI

CYP2C9

FDG

GGT

ADAMTS13

TIMP1

Proteintyrosine

phosphatase

Superoxidedismutase


or complex)

ioredoxin

TG2

BMPR2BNP

CD62

CD62E

PLJAMA

PAI1

Interleukins

Factor VIIa

MicroRNA134MMP20

MTHFR

SERPINC1

PVAPROS

SMARCAL1

Plasminogen

SCUBE1

PROC

NOS3

NPSA

PERC

Methemoglobin

Immunoglobulin

TPA

SERPINA1

SPARrombin

romboplastin

VKORC1

VV

PASP

Muscles

PATE

JAK2

KS1

TNFA

5lipoxygenase

PPARG

TNFR1Tyrosinase

PPARA

VCAM1

aFGF

Caspase 3MMP9

ATPase

IL8

Heparanase

Interleukin 5BFGF

Astragalus

IL2

PTP1B

ICAM1STAT1

SERCA2

MMP2PI3K

MMP1

G-CSF SAPS

Gracile



or complex)

AS160

AGT


or complex) ALDR


AMPK

A10

STAT3IL1B

ATF6

keap1T bet

ComplementC3

IL12

IL18CD45 AT2IL15

TelomeraseCCR5

MicroRNAs

CCL5

LDH


NFATc3

CD11c

Notch1

CD35

P glycoprotein

Myostatin

CD4

N33 CCL2

MUC1

Cyclindependent



CATMyosin

CAPE

Sulfatetransporters

CD69

Chymase

CD8

PHT1

IFNgamma

EC-NOS

p65

CD25

Protein kinase D1

TLR4


Radixpaeoniae

rubra

oxidases

Psoraleacorylifolia


Normal Model BFHX00

05

10

15

RL-m

ean

(cm

H2Omiddots

m)



00

05

10

15

20

25

lowast lowast

RL-m

ean

(cm

H2Omiddots

m)

(b)


002

004

006

Cdy

n-m

ean

(mlc

mH

2O

)

lowastlowast

lowastlowast


0

1

2

3

PEF

(mls

)

lowast lowastlowast

(d)




(a)


(b)




5 Discussion






(a)

Normal Model BFHX0

10

20

30

Mas

son

(per

area

)


(b)









(a)


(b)

Normal Model BFHX0

10000

20000

30000

HM

GB1

IOD



0

10000

20000

30000

40000

KGF

IOD

lowast lowast

(d)





6 Conclusion



Normal Model BFHX0

5000

10000

15000

20000

25000

TNF-

훼(p

gm

l)


Normal Model BFHX0

2000

4000

6000

8000

IL-1훽

(pg

ml)

lowastlowast lowast

Normal Model BFHX0

500

1000

1500IL

-17

(pg

ml)

lowast lowast

Normal Model BFHX0

2000

4000

6000

8000

IL-1

0 (p

gm

l)

lowastlowast lowast

0

2000

4000

6000

8000

10000

IL-6

(pg

ml)

Normal Model BFHX

lowastlowast lowast

0

100

200

300

400

500

IL-4

(pg

ml)

Normal Model BFHX

lowastlowastlowast


Normal Model BFHX0

1

2

3

IL-8


Normal Model BFHX00

01

02

03

04

05

IgA


Normal Model BFHX0

20

40

60

80

sIgA

BA

L (n

gm

l)




Competing Interests





References

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















HFABP

HMOX1Integrin


IFB BAL

IL10 p38

LTB4DH CA1HMOX

MAPK

CXCL12

IL4Bcl2

Pulmonary

embolism

cTnI

ASPS

CXCL4FGFR2

CRAT

CD309

ERA

PARPCYC

Complex I

CASP3

Monoamine

Smoothmuscle actin

CES1

VEGF

Albumin

Statins

IL6

CYP3A4

PSAP

BET1

ADM

APE

ANPB

ACPAArginase

FX

APC

CTPA

cTnT

Interferon

CRP

ARF

APS

ARG2

APOE

GPVI

CYP2C9

FDG

GGT

ADAMTS13

TIMP1

Proteintyrosine

phosphatase

Superoxidedismutase


or complex)

ioredoxin

TG2

BMPR2BNP

CD62

CD62E

PLJAMA

PAI1

Interleukins

Factor VIIa

MicroRNA134MMP20

MTHFR

SERPINC1

PVAPROS

SMARCAL1

Plasminogen

SCUBE1

PROC

NOS3

NPSA

PERC

Methemoglobin

Immunoglobulin

TPA

SERPINA1

SPARrombin

romboplastin

VKORC1

VV

PASP

Muscles

PATE

JAK2

KS1

TNFA

5lipoxygenase

PPARG

TNFR1Tyrosinase

PPARA

VCAM1

aFGF

Caspase 3MMP9

ATPase

IL8

Heparanase

Interleukin 5BFGF

Astragalus

IL2

PTP1B

ICAM1STAT1

SERCA2

MMP2PI3K

MMP1

G-CSF SAPS

Gracile



or complex)

AS160

AGT


or complex) ALDR


AMPK

A10

STAT3IL1B

ATF6

keap1T bet

ComplementC3

IL12

IL18CD45 AT2IL15

TelomeraseCCR5

MicroRNAs

CCL5

LDH


NFATc3

CD11c

Notch1

CD35

P glycoprotein

Myostatin

CD4

N33 CCL2

MUC1

Cyclindependent



CATMyosin

CAPE

Sulfatetransporters

CD69

Chymase

CD8

PHT1

IFNgamma

EC-NOS

p65

CD25

Protein kinase D1

TLR4


Radixpaeoniae

rubra

oxidases

Psoraleacorylifolia


Normal Model BFHX00

05

10

15

RL-m

ean

(cm

H2Omiddots

m)



00

05

10

15

20

25

lowast lowast

RL-m

ean

(cm

H2Omiddots

m)

(b)


002

004

006

Cdy

n-m

ean

(mlc

mH

2O

)

lowastlowast

lowastlowast


0

1

2

3

PEF

(mls

)

lowast lowastlowast

(d)




(a)


(b)




5 Discussion






(a)

Normal Model BFHX0

10

20

30

Mas

son

(per

area

)


(b)









(a)


(b)

Normal Model BFHX0

10000

20000

30000

HM

GB1

IOD



0

10000

20000

30000

40000

KGF

IOD

lowast lowast

(d)





6 Conclusion



Normal Model BFHX0

5000

10000

15000

20000

25000

TNF-

훼(p

gm

l)


Normal Model BFHX0

2000

4000

6000

8000

IL-1훽

(pg

ml)

lowastlowast lowast

Normal Model BFHX0

500

1000

1500IL

-17

(pg

ml)

lowast lowast

Normal Model BFHX0

2000

4000

6000

8000

IL-1

0 (p

gm

l)

lowastlowast lowast

0

2000

4000

6000

8000

10000

IL-6

(pg

ml)

Normal Model BFHX

lowastlowast lowast

0

100

200

300

400

500

IL-4

(pg

ml)

Normal Model BFHX

lowastlowastlowast


Normal Model BFHX0

1

2

3

IL-8


Normal Model BFHX00

01

02

03

04

05

IgA


Normal Model BFHX0

20

40

60

80

sIgA

BA

L (n

gm

l)




Competing Interests





References

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















(a)


(b)




5 Discussion






(a)

Normal Model BFHX0

10

20

30

Mas

son

(per

area

)


(b)









(a)


(b)

Normal Model BFHX0

10000

20000

30000

HM

GB1

IOD



0

10000

20000

30000

40000

KGF

IOD

lowast lowast

(d)





6 Conclusion



Normal Model BFHX0

5000

10000

15000

20000

25000

TNF-

훼(p

gm

l)


Normal Model BFHX0

2000

4000

6000

8000

IL-1훽

(pg

ml)

lowastlowast lowast

Normal Model BFHX0

500

1000

1500IL

-17

(pg

ml)

lowast lowast

Normal Model BFHX0

2000

4000

6000

8000

IL-1

0 (p

gm

l)

lowastlowast lowast

0

2000

4000

6000

8000

10000

IL-6

(pg

ml)

Normal Model BFHX

lowastlowast lowast

0

100

200

300

400

500

IL-4

(pg

ml)

Normal Model BFHX

lowastlowastlowast


Normal Model BFHX0

1

2

3

IL-8


Normal Model BFHX00

01

02

03

04

05

IgA


Normal Model BFHX0

20

40

60

80

sIgA

BA

L (n

gm

l)




Competing Interests





References

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















(a)

Normal Model BFHX0

10

20

30

Mas

son

(per

area

)


(b)









(a)


(b)

Normal Model BFHX0

10000

20000

30000

HM

GB1

IOD



0

10000

20000

30000

40000

KGF

IOD

lowast lowast

(d)





6 Conclusion



Normal Model BFHX0

5000

10000

15000

20000

25000

TNF-

훼(p

gm

l)


Normal Model BFHX0

2000

4000

6000

8000

IL-1훽

(pg

ml)

lowastlowast lowast

Normal Model BFHX0

500

1000

1500IL

-17

(pg

ml)

lowast lowast

Normal Model BFHX0

2000

4000

6000

8000

IL-1

0 (p

gm

l)

lowastlowast lowast

0

2000

4000

6000

8000

10000

IL-6

(pg

ml)

Normal Model BFHX

lowastlowast lowast

0

100

200

300

400

500

IL-4

(pg

ml)

Normal Model BFHX

lowastlowastlowast


Normal Model BFHX0

1

2

3

IL-8


Normal Model BFHX00

01

02

03

04

05

IgA


Normal Model BFHX0

20

40

60

80

sIgA

BA

L (n

gm

l)




Competing Interests





References

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















(a)


(b)

Normal Model BFHX0

10000

20000

30000

HM

GB1

IOD



0

10000

20000

30000

40000

KGF

IOD

lowast lowast

(d)





6 Conclusion



Normal Model BFHX0

5000

10000

15000

20000

25000

TNF-

훼(p

gm

l)


Normal Model BFHX0

2000

4000

6000

8000

IL-1훽

(pg

ml)

lowastlowast lowast

Normal Model BFHX0

500

1000

1500IL

-17

(pg

ml)

lowast lowast

Normal Model BFHX0

2000

4000

6000

8000

IL-1

0 (p

gm

l)

lowastlowast lowast

0

2000

4000

6000

8000

10000

IL-6

(pg

ml)

Normal Model BFHX

lowastlowast lowast

0

100

200

300

400

500

IL-4

(pg

ml)

Normal Model BFHX

lowastlowastlowast


Normal Model BFHX0

1

2

3

IL-8


Normal Model BFHX00

01

02

03

04

05

IgA


Normal Model BFHX0

20

40

60

80

sIgA

BA

L (n

gm

l)




Competing Interests





References

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Normal Model BFHX0

5000

10000

15000

20000

25000

TNF-

훼(p

gm

l)


Normal Model BFHX0

2000

4000

6000

8000

IL-1훽

(pg

ml)

lowastlowast lowast

Normal Model BFHX0

500

1000

1500IL

-17

(pg

ml)

lowast lowast

Normal Model BFHX0

2000

4000

6000

8000

IL-1

0 (p

gm

l)

lowastlowast lowast

0

2000

4000

6000

8000

10000

IL-6

(pg

ml)

Normal Model BFHX

lowastlowast lowast

0

100

200

300

400

500

IL-4

(pg

ml)

Normal Model BFHX

lowastlowastlowast


Normal Model BFHX0

1

2

3

IL-8


Normal Model BFHX00

01

02

03

04

05

IgA


Normal Model BFHX0

20

40

60

80

sIgA

BA

L (n

gm

l)




Competing Interests





References

















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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