M Denis, L Guojian, M Widmer and A Cantin
Pulmonary Research Unit, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.

Mice of the C57BL/6 strain were injected with bacterial lipopolysaccharide (LPS) followed by formylnorleucyl-leucyl- phenylalanine (FNLP) by the intraperitoneal route; markers of acute lung injury were examined in mice given a fusion protein of soluble human tumor necrosis factor-alpha (TNF-alpha) receptor (p80) linked to the Fc portion of human IgG (TNFR:Fc) or excipient. Challenge with LPS/FNLP elicited an adult respiratory distress syndrome-like pathology characterized by sharp increases in levels of lactate dehydrogenase (LDH) and total proteins in bronchoalveolar lavage as well as in lung myeloperoxidase (MPO) content at 16 and 20 h after challenge. Infusion of 1 mg of TNFR:Fc 2 h before challenge very significantly abrogated the increases in LDH, protein levels, and MPO. Histologic analysis revealed that LPS/FNLP infusion resulted in an intravascular neutrophil agglomerate and perivascular/peribronchial damage; the extent of tissue lesions was significantly reduced, but not abrogated, by TNF-alpha depletion. There were moderate levels of antigenic TNF-alpha in lung homogenates at 16 and 20 h after challenge, not affected by infusion with TNFR:Fc. No bioactive TNF-alpha was detected in lung homogenates of challenged mice given TNFR:Fc. High levels of antigenic interleukin- 6 (IL-6) were found in lung homogenates of challenged mice treated with TNFR:Fc or with diluent. Elevated levels of antigenic IL-6 and TNF- alpha were found in sera of challenged mice at 16 and 20 h after injection; TNFR:Fc-treated mice had a higher level of antigenic TNF- alpha than did challenged mice given diluent, but it was not bioactive.(ABSTRACT TRUNCATED AT 250 WORDS)

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