In previous studies, we have shown that C-reactive protein (CRP) inhibits chemotaxis of neutrophils to complement fragments in vitro. To evaluate the effect of CRP on C5a-induced inflammation in vivo, a rabbit model of alveolitis was used. Rabbits pretreated with subcutaneous injections of croton oil had serum CRP increase from undetectable levels to 270 +/- 70 micrograms/ml 48 hours later. Rabbits were intubated and C5a des arg (10 micrograms/ml) instilled directly into the lungs via an endotracheal tube. Four to six hours later, the animals were killed and bronchoalveolar lavage performed. Rabbits pretreated with croton oil had significantly (P < 0.01) reduced C5a des arg-stimulated neutrophil infiltration (30 +/- 5%) into alveolar air spaces compared to untreated rabbits (64 +/- 9%). Increased numbers of total leukocytes in the alveolar washes coincided with increased neutrophil numbers whereas alveolar macrophages remained unchanged in all groups. Rabbits pretreated with croton oil also had a significant decrease (P < 0.05) in total protein (320 +/- 50 micrograms/ml) in lavage fluid after C5a instillation compared with untreated animals (850 +/- 140 micrograms/ml). In vitro, rabbit CRP (50 micrograms/ml) added to normal rabbit serum significantly (P < 0.05) inhibited chemotaxis of human neutrophils by 41%. Finally, direct intravenous pretreatment of rabbits with purified CRP also significantly reduced C5a-induced alveolitis. The CRP-C5a group had 33 +/- 10% neutrophil infiltration, a significant (P < 0.01) reduction from the C5a group (71 +/- 6%). The total protein content of the CRP-C5a rabbits was 986 +/- 165 micrograms/ml in the lavage fluid, which was significantly (P < 0.05) lower than the C5a group (1645 +/- 363 micrograms/ml). Therefore, CRP inhibits the development of neutrophil alveolitis and protein leakage in vivo and inhibits neutrophil chemotaxis in vitro. These data indicate that CRP offers a protective effect in neutrophil-mediated lung injury by reducing neutrophil influx and protein leak.