J Infect Dis.-2000-Hang-1738-48
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Figure 7. Neutrophil accumulation in the tissues of murine interleukin-8 receptor homologue (mIL-8Rh) knockout (KO) mice after 35 days.Sections were obtained from mIL-8Rh KO mice 35 days after inoculation and were stained with RB6-8C5 antibody, to detect neutrophils. A,Section from the renal medulla. B, Section from the renal cortex. Magnification, 3200.
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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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