Clara cell secretory protein-deficient mice differ from wild-type mice in inflammatory chemokine expression to oxygen and ozone, but not to endotoxin

The in vivo function of Clara cell secretory protein (CCSP) is unknown. Bio logic and biochemical properties associated with CCSP have led to speculati on that it participates in pulmonary inflammatory control. Our earlier stud ies have demonstrated that CCSP-deficient mice are more sensitive to either hyperoxia or ozone toxicity and show altered oxidant-induced pulmonary pro inflammatory responses. In this study we test the hypothesis that altered c hemokine responses seen in CCSP-/- mice following oxidant stress are a dire ct consequence of altered immunoregulation associated with CCSP deficiency. lo test this hypothesis we utilized three distinct models of inducing pulm onary toxicity: hyperoxia and ozone (O-3), which cause epithelial cell inju ry, and endotoxin, which causes pulmonary inflammation independent of direc t epithelial cell injury. Wild-type (WT) or CCSP-/- strain 129 mice were ex posed to O-3 at 1.0 ppm for 24 hours, oxygen (O-2) > 99% for 68 hours or in halation of 0.0575 mu g endotoxin per mouse for 10 minutes and examined 6 h ours postexposure. Mire displayed increased sensitivity to O-3, as demonstr ated by increased abundance of mRNAs encoding Eotaxin, macrophage inflammat ory protein (MIP)-1 alpha, and MIP-2, after 4 hours of exposure, whereas WT mice were unaltered from controls. Increased sensitivity to hyperoxia was also observed, as demonstrated by increased abundance of mRNAs Encoding Eot axin, MIP-1 alpha, MIP-1 beta, MIP-2, and interferon-gamma inducible (IP)-1 0 after 68 hours of exposure, whereas WT mice were unaltered from controls. In contrast, WT and CCSP-/- mice responded identically 6 hours postinhalat ion of 0.0575 mu g lipopolysaccharide (LPS) per mouse. PMN response was 63% and 64% in WT anti CCSP-/- mice, respectively. Messenger RNAs Encoding Eot axin, MIP-1 alpha, MIP-1 beta, MIP-2, IP-10, and MCP-1 mere increased ident ically. We conclude that CCSP does not participate in regulation of the end otoxin-elicited pulmonary inflammatory response. Identical inflammatory and chemokine responses of CCSP-/- and WT mire in response to a nonepithelial toxic agent (endotoxin) suggest that altered inflammatory control observed between Till and CCSP-/- mice following O-2 and O-3 exposure is not the res ult of altered immunoregulation.