Chronic Conditions in Older Adults and Susceptibility to Environmental Exposures Mark W. Frampton MD...

Chronic Conditions in Older Adults and Susceptibility to Environmental

Exposures

Mark W. Frampton MD

Pulmonary & Critical Care Division

University of Rochester Medical Center

Questions About Susceptibility to Air Pollution in the Elderly

• What are the conditions involved?

• How does air pollution affect patients with these conditions?

• Can air pollution cause these conditions?

Diseases of Concern

• Obstructive Lung Disease

• Cardiovascular disease

• Infection

• Cancer

• Others that haven’t been studied?– Obstructive sleep apnea– Pulmonary fibrosis– Chronic cough

Obstructive Lung Diseases

• Asthma

• COPD, Chronic Bronchitis

• Cystic Fibrosis

• Smoking?

The Normal Airway

Mucosal Inflammation

Increased Secretions

The Airway in Asthma

Spirometry Flow-Volume LoopNormal COPD

Dosimetry & Fate of Deposited PM

NORMAL

COPD

PM Xenon

0

0.05

0.1

0.15

0.2

0.25

0.3

Normal

SAD

CO

PD

Diameter = 1 µm

Smoker

Asthma

Fractional Deposition

Bennett et al., 1993, 2002 Kim et al., 1997

Rest Exercise0

0.2

0.4

0.6

0.8

1Healthy

Asthma

p<0.001

Total Respiratory Deposition of UFP

p<0.001

Respiratory Deposition of UFP

Cardiovascular Disease

• Atherosclerosis• Coronary artery disease• Myocardial infarction• Congestive heart failure• Cardiac arrhythmias• Peripheral vascular disease• Diabetes• Pulmonary hypertension

Increase in Atherosclerosis with 10 µg/m3 increase in

PM2.5

Künzli et al., EHP 2004

Canine Myocardial Ischemia Model

• Implantation of balloon occluder for coronary artery occlusion

• 5 min occlusions with CAPs or Sham exposures.

Wellenius et al., 2002

Wellenius et al., 2002

Endothelial Dysfunction in AtherosclerosisRoss et al., NEJM 1999

Early AtherosclerosisDiaz et al., NEJM 1997

How do inhaled particles cause effects in blood vessels?

Science, 2005

Does exposure to UFP alter endothelial function in the pulmonary circulation?

Exposure to Carbon UFP

• Count median diameter ~26 nm, GSD ~1.6

• 2 hrs by mouthpiece

• Intermittent exercise

Experimental Protocol

-2 0 2 4 6 24 48

UFP or Air

SymptomsPhlebotomyExhaled NODLCOSpirometryOximetry

= Resting HRVFlow-mediated dilatation

=

Leukocyte Recruitment in Inflammation

Inflammation: The Leukocyte Adhesion Cascade

Inflammation is a defense reaction caused by tissue damage or injury, characterized by redness, heat, swelling, and pain. The primary objective of inflammation is to localize and eradicate the irritant and repair the surrounding tissue. For the survival of the host, inflammation is a necessary and beneficial process. The inflammatory response involves three major stages: first, dilation of capillaries to increase blood flow; second, microvascular structural changes and escape of plasma proteins from the bloodstream; and third, leukocyte transmigration through endothelium and accumulation at the site of injury.

The leukocyte adhesion cascade is a sequence of adhesion and activation events that ends with extravasation of the leukocyte, whereby the cell exerts its effects on the inflamed site. At least five steps of the adhesion cascade are , ,

, , and . Each of these five steps appears to be necessary for effective leukocyte recruitment, because blocking any of the five can severely reduce leukocyte accumulation in the tissue. These steps are not phases of inflammation, but represent the sequence of events from the perspective of each leukocyte. At any given moment, capture, rolling, slow rolling, firm adhesion and transmigration all happen in parallel, involving different leukocytes in the same microvessels.

capture rolling slow rolling firm adhesion transmigration

The roles of adhesion molecules in acute and chronic inflammation have been investigated using model systems and microcirculation studies. The ultimate goal of inflammation research is to develop methods to control inflammation by

modulating or blocking leukocyte adhesion to the endothelium. These ideas developed by basic research contribute to contemporary research projects developing . Anti-inflammatory agents function as blockers, suppressors, or modulators of the inflammatory response.

in vitro in vivo

anti- inflammatory drugs

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11/3/03 4:20 PMUntitled Document

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Pulmonary Diffusing Capacity for CO (DLCO):

Sensitive to changes in pulmonary capillary blood volume

*

Ch

ang

e in

DL

CO

(m

l/min

/mm

Hg

)

-3

-2

-1

0

1

Air

UFP

21 h 45 h

Change in CO Diffusion Capacity After Exposure to 50 mg/m3 UFP

Does exposure to UFP alter endothelial function in the systemic circulation?

Systemic Endothelial Function:Flow-Mediated Vasodilatation

AM

PM

Monocyte

NO

OONO-

CD11a/CD18

TFTF

Fibrin &platelet deposition

Before Exposure

After Exposure

NO

Platelets

Proposed Mechanisms for Vascular Effects of UFP

Conclusions: PM Effects on Chronic Conditions in the Elderly

• PM exacerbates obstructive lung disease• PM triggers cardiac events• PM may alter pulmonary & systemic

endothelial function• PM may accelerate atherosclerosis• The key PM characteristics remain

unknown• Likely other affected conditions