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Inverse relationship between severity of experimental pyelonephritis and nitric oxide production in C3H/HeJ mice
1Departments of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA. bnowicki@marlin.utmb.edu
Abstract:
The contribution of nitric oxide to host resistance to experimental pyelonephritis is not well understood. We examined whether the inhibition of nitric oxide synthesis alters the sensitivity of lipopolysaccharide (LPS) responder (C3H/HeN) and nonresponder (C3H/HeJ) mice to experimental Escherichia coli pyelonephritis. C3H/HeJ and C3H/HeN mice were implanted subcutaneously with minipumps containing an inhibitor of nitric oxide, NG-nitro-L-arginine methyl ester (L-NAME), or a corresponding vehicle. Ascending urinary tract infection by bladder catheterization with two strains of E. coli, an O75 strain bearing Dr fimbriae and an O75 strain bearing P fimbriae, was developed in tested animals. Twenty-four hours following bladder infection, the kidneys of C3H/HeN and C3H/HeJ mice were colonized at a similar rate. However, 5 weeks postinoculation, C3H/HeN mice cleared infection while C3H/HeJ mice showed persistent colonization. Twenty-four hours following infection, C3H/HeN mice treated with L-NAME showed no significant increase of renal tissue infection compared to the saline-treated control group. However, L-NAME-treated C3H/HeJ mice showed an approximately 100-fold increase in E. coli infection rate compared to the saline-treated controls in the Dr+ group but showed no change compared to those in the P+ group. Dissemination of Dr+ E. coli but not P+ E. coli to the liver and uterus was significantly enhanced with L-NAME treatment in C3H/HeJ mice only. Nitric oxide had no direct killing effect on E. coli in vitro. Nitrite production by various organs was found to be significantly lower in C3H/HeJ mice than in C3H/HeN mice. Alteration of nitric oxide and LPS responsiveness was significantly associated with the increased sensitivity of C3H/HeJ mice to experimental Dr+ but not to P+ E. coli pyelonephritis. These findings are consistent with the hypothesis that nitric oxide synthase activity in concert with LPS responsiveness may participate in the antibacterial defense mechanisms of the C3H mouse urinary tract. This phenomenon is strain dependent and possibly related to the invasive properties of E. coli.
Insights
Nitric oxide inhibition increased susceptibility to E. coli pyelonephritis in LPS-nonresponder mice, particularly with Dr+ E. coli. This suggests nitric oxide and LPS responsiveness are key to urinary tract defense against specific E. coli strains.
Area of Science:
- Immunology
- Microbiology
- Urology
Background:
- Nitric oxide's role in host resistance to pyelonephritis is unclear.
- Lipopolysaccharide (LPS) responder (C3H/HeN) and nonresponder (C3H/HeJ) mice exhibit different responses to bacterial infections.
Purpose of the Study:
- To investigate if inhibiting nitric oxide synthesis affects experimental pyelonephritis susceptibility in LPS-responder and nonresponder mice.
- To determine the influence of nitric oxide inhibition on E. coli colonization and dissemination in different mouse strains.
Main Methods:
- Mice (C3H/HeN and C3H/HeJ) were treated with NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthesis inhibitor, or a vehicle.
- Mice were infected with Dr+ or P+ fimbriated E. coli strains via bladder catheterization.
- Bacterial colonization in kidneys, liver, and uterus was assessed at 24 hours and 5 weeks post-infection.
Main Results:
- C3H/HeN mice cleared E. coli infection, while C3H/HeJ mice showed persistent colonization.
- L-NAME treatment significantly increased renal E. coli infection in C3H/HeJ mice challenged with Dr+ E. coli, but not P+ E. coli.
- Dissemination of Dr+ E. coli to the liver and uterus was enhanced by L-NAME in C3H/HeJ mice.
Conclusions:
- Nitric oxide synthase activity, in conjunction with LPS responsiveness, contributes to urinary tract defense against specific E. coli strains.
- The protective effect of nitric oxide is strain-dependent and linked to E. coli's invasive properties.