JID 2000;182 (December) IL-8 Receptor KO Mice and Neutrophil
Entrapment 1747
Figure 8. Trichrome staining for fibrosis in kidneys of Balb/c
controland murine interleukin-8 receptor homologue (mIL-8Rh) KO
mice.Arrows show blue areas indicating fibrosis. Magnification,
3100.
edema, with an increase in overall size, hyperemia,
neutrophilinflux, and the formation of abscesses that were visible
to thenaked eye. Tissue sections of these areas showed
accumulationof neutrophils but little destruction of surrounding
tissue. Theacute changes were followed by chronic tissue damage in
themIL-8Rh KO mice. After 35 days, a reduction in overall renalsize
occurred, and the kidneys were pale, reflecting a reducedblood
flow. Areas of scar tissue caused an irregular kidneyoutline. There
was parenchymal thinning, with loss of corticaltissue in large
areas, as well as fibrosis and diffuse inflammatory
infiltrates. These acute and chronic changes make the mIL-8RhKO
mice a unique model for studying the natural history andmechanisms
of renal scarring.
Several experimental approaches have been taken to studythe
mechanisms of renal scarring. Earlier models have requiredsurgical
manipulations or other invasive procedures to renderthe tissues
vulnerable to infection [23, 24]. Anti-inflammatorydrugs or oxygen
radical scavengers have been used to modifythe inflammatory
response to UTI and to link the inflammatoryresponse to the
scarring process [17], but tools to directly ad-dress the role of
neutrophils have not been used. Different lym-phocyte populations
accumulate in the kidney, and immuno-logic mechanisms have been
proposed to contribute to tissuedestruction [23, 25]. Our findings
show that the chemokinereceptor dysfunction renders the mIL-8Rh KO
mice susceptibleto UTI, and that dysfunctional neutrophil
recruitment into thekidney is a powerful mechanism of tissue
destruction.
About 30% of children with acute pyelonephritis have
>1recurrence, and, of them, 60% continue to recur, and somego on
to develop renal scarring [26]. The defects that renderthese
patients susceptible to infection and the molecular mech-anisms of
renal scarring are poorly understood. The presentstudy suggests
that defects in chemokine receptor expressioncause dysfunctional
neutrophil migration and tissue damage.In preliminary studies, we
examined chemokine receptor ex-pression on neutrophils from
children with recurrent UTI andrenal scarring. These studies
demonstrated that cell surface ex-pression of the CXCR1 receptor is
low in children with recur-rent episodes of acute pyelonephritis,
compared with age-matched controls [10].
The following scenario may now be proposed. Infection ofthe
urinary tract triggers the secretion of epithelial chemokinesand
expression of chemokine receptors. Neutrophils are re-cruited into
the kidneys and bladders and kill the bacteria ontheir way through
the tissues. There is no tissue damage as theneutrophils rapidly
cross the mucosal barrier and are excretedin the urine. In the
absence of functional chemokine receptors,neutrophils are trapped,
tissues are damaged, and renal scarringmay develop. In addition,
the clearance of bacteria from thetissues is impaired. We have
shown that one specific moleculardeficiency may underlie both
disease susceptibility and the ten-dency to develop tissue
pathology. In addition, the results un-derline the important role
of innate defense mechanisms in boththe prevention and promotion of
disease. This work thereforeprovides a new approach for studying
the pathogenesis of scar-ring and to understand its basis in this
important group ofpatients.
Acknowledgments
We thank P. Alm (Dept. of Pathology, Lund University, Lund,
Swe-den) for assistance with the staining for fibrosis in figure
8.
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1748 Hang et al. JID 2000;182 (December)
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