IFNγ prolongs survival in experimental Escherichia coli pyelonephritis: implications for favorable phagocytosis

Introduction

IFNγ is a promising immunomodulator in sepsis because it is thought it may reverse immunoparalysis and improve phagocytosis. Its effect was investigated in experimental pyelonephritis and sepsis.

Methods

Experimental pyelonephritis by Escherichia coli was induced in 18 rabbits after ligation of the right pelvo-ureteral junction and infusion of one 1 × 10⁷ log-phase cfu/ml inoculum above the ligation. Animals were assigned into 10 controls (group A) and into eight administered intravenously 0.1 μg/kg IFNγ 30 minutes after bacterial challenge (group B). Blood was sampled at serial time intervals; quantitative cultures were done; apoptosis of lymphocytes and of monocytes was assessed by flow cytometry; malondialdehyde (MDA) was estimated by the thiobarbiturate assay and passage through an HPLC system. After death, quantitative tissue cultures were done.

Results

Median survival of group A was 3 days and of group B was 18 days (log-rank: 4.858, P = 0.028). Mean log₁₀ of bacteria in blood for groups A and B at 2 hours was 1.59 and 1.21 (P = NS); at 4 hours 1.61 and 1.97 (P = NS); at 24 hours 1.28 and 1.02; and at 48 hours 1.29 and 1.00 (P = NS). Respective rates of apoptosis of lymphocytes at 2 hours were 17.1 and 22.2% (P = NS); at 4 hours 17.9 and 24.0% (P = NS); at 24 hours 18.3 and 21.9% (P = NS); and at 48 hours 20.5 and 22.8% (P = NS). Respective rates of apoptosis of monocytes at 2 hours were 32.8 and 36.0% (P = NS); at 4 hours 42.8 and 39.3% (P = NS); at 24 hours 54.5 and 62.1% (P = NS); and at 48 hours 52.5 and 64.3% (P = 0.042). Respective median serum MDA of groups A and B were 1.05 and 2.06 μmol/ml at baseline (P = NS); 0.93 and 2.54 μmol/ml at 2 hours (p: 0.028); 2.30 and 1.02 μmol/ml at 4 hours (P = NS); 1.47 and 2.05 μmol/ml at 24 hours (P = NS); and 1.71 and 1.85 μmol/ml at 48 hours (P = NS). Mean log₁₀ of bacterial growth in the liver of group A and of group B on sacrifice was 3.47 and 1.32, respectively (P = 0.043); and in the right kidney was 5.78 and 1.94, respectively (P = 0.004).

Conclusions

IFNγ prolongs survival when administered after induction of experimental pyelonephritis by E. coli. Its effect is mediated through: enhanced phagocytosis as evidenced by increase of oxidant stress and decrease of tissue bacterial load; and modulation of inflammation as evidenced by increase of apoptosis of monocytes.