Urinary tract infection and renal scarring

University dissertation from Stockholm : Karolinska Institutet, Microbiology and Tumor Biology Center (MTC)

Abstract: Urinary tract infection (UTI) is the most common bacterial infection. Although most patients with UTI have a good prognosis, there is a risk of serious complications in a group of them. In up to 40% of the cases of infection of the upper urinary tract, pyelonephritis, renal scar develops and the scarring process may occasionally lead to chronic renal insufficiency. Moreover, UTI has a high tendency of recurrence and recurrent UTis even increase the risk of renal scarring. We have been studying several mechanisms in the pathogenesis of UTI and renal scarring. We described the production of cathelicidin, an endogenous antibiotic, in the epithelial cells of the urinary tract. Although present in low concentrations constitutively, after bacterial attachment the epithelial cells rapidly increased the cathelicidin synthesis and release. Genedeficient mice confirmed the relevance of the epithelial cathelicidin for the protection of the urinary tract against attaching bacteria. Bacteria, however, seemed to develop strategies to overcome the 'protective shield' of cathelicidin. We showed that the majority of uropathogenic E. coli are able to produce curli firnbriae and cellulose and thus form a multicellular community, biofilm. This tactic helps bacteria adhere to the epithelium without stimulation of the immune system, invade the cells, and be protected from cathelicidin. The low levels of cathelicidin, on the other hand, inhibit the formation of biofilm, and protect the urinary tract also against this form of bacterial virulence. Despite the effective antimicrobial defense of the urinary tract, bacteria sometimes win the 'first battle' against mucosal immunity and persist or invade the host. Then, more intense inflammation is needed with involvement of professional immune cells and with some inevitable degree of tissue damage. Cathelicidin is also an important player in these immune processes, in the recruitment of neutrophils and neutrophil-mediated killing of bacteria. During inflammation in the kidney, many proteases and their inhibitors, amongst them MMP-9 and TIMP-1, are produced. Our data suggested that the delicate balance between MNIP-9 and TIMP-1 determines the intensity of inflammation, degree of tissue destruction and proper healing after infection. If too high levels of TIMP- 1 are produced during acute inflammation, renal scar will develop more probably. We indicated that the pro-scarring effect of TIMP-1 could be explained by its complex action during the acute inflammation. TIMP-1 prolongs the stay of granulocytes in the tissue by inhibiting their apoptosis and migration into urine. Moreover, TIMP- 1 stimulates respiratory burst of neutrophils. 'Entrapped' and activated granulocytes may extensively destroy the tissue and trigger renal scarring. Data presented in this thesis describe mechanisms in the pathogenesis of urinary tract infection and postinfective renal scarring. They also open new possibilities for treatment in order to protect the urinary tract from bacteria and the kidney from damage.

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