INFLUENCE OF AN ESTABLISHED ACUTE-PHASE RESPONSE ON THE SEVERITY OF EXPERIMENTAL NEPHRITIS

Small doses of lipopolysaccharide (LPS) induce an acute phase response (APR), and a number of studies have also shown that this greatly enha nces the severity of glomerular injury in the heterologous phase of ne phrotoxic nephritis (hNTN), an experimental model of anti-glomerular b asement membrane (GBM) disease. Here, we examined the influence of pre -existing subclinical infection and raised APR, assessed by plasma alp ha(2)-macroglobulin (alpha(2)-M) concentration, on the degree of injur y in this model of nephritis. Studies were initially performed to dete rmine 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 f ound to be variable and dependent on the weight of the rats. Single in jections of either LPS or IL-6 had a comparable effect, and continuous perfusions of LPS caused a progressive increase in alpha(2)-M which p eaked 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 1 6 +/- 4 mg/24 h (P < 0.001), respectively. However, all these rats rem ained active and none of them died. In contrast, injection of 0.25 mu g LPS before induction of nephritis with 10 mg anti-GBM antibody, in r ats with raised alpha(2)-M, caused severe albuminuria (115 +/- 23 mg/2 4 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 resu lts demonstrate the potential effect of pre-existing subclinical infec tion and raised APR on severity of glomerular injury which may affect the outcome of experimental studies.