The polymorphonuclear neutrophil (PMN) serves a critical role in the lung as a principal component in acute host defense. However, a number of lung diseases, including chronic bronchitis/ chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma and cystic fibrosis display a pathologic inflammatory component where neutrophils are destructive to lung tissue. Our principal hypothesis, that the C5a anaphylatoxin and the chemokine IL-8 represent the dominant chemoattractants mediating neutrophil trafficking to the lung, has been supported by our initial studies with mice genetically altered to be deficient in chemoattractant receptors. A non-redundant role for C5a and its receptor was identified in two models of lung inflammation. C5a receptor (C5aR) deficient mice are completely protected from immune complex-mediated lung injury, while they are rendered incapable of clearing intrapulmonary pseudomonas aeruginosa despite a vigorous inflammatory infiltrate. The present competing renewal grant seeks to continue these studies, which will identify the specific roles played by the C5a and IL-8 ligand receptor pairs using a molecular genetic approach.
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