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. Biologic and biochemical properties associated with CCSP have led to speculation that it participates in pulmonary inflammatory control. Our earlier studies have demonstrated that CCSP-deficient mice are more sensitive to either hyperoxia or ozone toxicity and show altered oxidant-induced pulmonary proinflammatory responses. In this study we test the hypothesis that altered chemokine responses seen in CCSP-/- mice following oxidant stress are a direct consequence of altered immunoregulation associated with CCSP deficiency. lo test this hypothesis we utilized three distinct models of inducing pulmonary toxicity: hyperoxia and ozone (O-3), which cause epithelial cell injury, and endotoxin, which causes pulmonary inflammation independent of direct epithelial cell injury. Wild-type (WT) or CCSP-/- strain 129 mice were exposed to O-3 at 1.0 ppm for 24 hours, oxygen (O-2) > 99% for 68 hours or inhalation of 0.0575 mu g endotoxin per mouse for 10 minutes and examined 6 hours postexposure. Mire displayed increased sensitivity to O-3, as demonstrated by increased abundance of mRNAs encoding Eotaxin, macrophage inflammatory 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 Eotaxin, MIP-1 alpha, MIP-1 beta, MIP-2, and interferon-gamma inducible (IP)-10 after 68 hours of exposure, whereas WT mice were unaltered from controls. In contrast, WT and CCSP-/- mice responded identically 6 hours postinhalation of 0.0575 mu g lipopolysaccharide (LPS) per mouse. PMN response was 63% and 64% in WT anti CCSP-/- mice, respectively. Messenger RNAs Encoding Eotaxin, MIP-1 alpha, MIP-1 beta, MIP-2, IP-10, and MCP-1 mere increased identically. We conclude that CCSP does not participate in regulation of the endotoxin-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 result of altered immunoregulation.