Influence of an established acute phase response on the severity of experimental nephritis

Abstract

SUMMARY: Small doses of lipopolysaccharide (LPS) induce an acute phase response (APR), and a number of studies have also shown that this greatly enhances the severity of glomerular injury in the heterologous phase of nephrotoxic nephritis (hNTN), an experimental model of anuglomerular basement membrane (GBM) disease. Here, we examined the influence of pre-existing subclinical infection and raised APR assessed by plasma α2-macrogiobulin (α2-M) concentration, on the degree of injury in this model of nephritis. Studies were initially performed to determine the normal range of α2-M in rats and its modulation by IL-6 and different doses of LPS. Plasma concentration of α2-M was found to be variable and dependent on the weight of the rats. Single injections of either LPS or IL-6 had a comparable effect and continuous perfusions of LPS caused a progressive increase in α2-M which peaked al 4S h and declined gradually over 1 week. Following induction of nephritis with long of anti-GBM antibody, rats with raised α2-M had 14 ± 3 mg 24 h albuminuria compared with 4 ± 1 mg 24 h in rats with normal α2-M (P < 0.0.001, Wilcoxon). Injection of 20 mg anti-GBM antibody caused 36 ± 11 mg 24 h albuminuria compared with 16 ± 4 mg/24h (P < 0001), respectively. However, all these rats remained active and none of them died, hi contrast, injection of 0.25 μg LPS before induction of nephritis with 10 mg anti-(IBM antibody, in rats with raised a,-M, caused severe albuminuria (115 ± 23 mg 24 h) compared wilh rats having normal levels of α2-M (72 ± 15 mg 24h. P < 005), Furthermore, rats with raised α2-M also had severe systemic manifestations characterized by pulmonary haemorrhage and extensive glomerular thrombosis, and many of them died. These results demonstrate the potential effect of pre-existing subclinical infection and raised APR on severity of glomerular injury which may affect the outcome of experimental studies.