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

Small doses of lipopolysaccharide (LPS) induced 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 anti-glomerular basement membrane (GBM) disease. Here, we examined the influence of pre-existing subclinical infection and raised APR, assessed by plasma alpha 2-macroglobulin (alpha 2-M) concentration, on the degree of injury in this model of nephritis. Studies were initially performed to determine the normal range of alpha 2-M in rats and its modulation by IL-6 and different doses of LPS. Plasma concentration of alpha 2-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 alpha 2-M which peaked at 48 h and declined gradually over 1 week. Following induction of nephritis with 10 mg of anti-GBM antibody, rats with raised alpha 2-M had 14 +/- 3 mg/24 h albuminuria compared with 4 +/- 1 mg/24 h in rats with normal alpha 2-M (P < 0.001, Wilcoxon). Injection of 20 mg anti-GBM antibody caused 36 +/- 11 mg/24 h albuminuria compared with 16 +/- 4 mg/24 h (P < 0.001), respectively. However, all these rats remained active and none of them died. In contrast, injection of 0.25 microgram LPS before induction of nephritis with 10 mg anti-GBM antibody, in rats with raised alpha 2-M, caused severe albuminuria (115 +/- 23 mg/24 h) compared with rats having normal levels of alpha 2-M (72 +/- 15 mg/24 h, P < 0.05). Furthermore, rats with raised alpha 2-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.