The objectives of this proposal are to continue investigations into the mechanisms by which inflammatory reactions occurring in the lung result in connective tissue damage. These studies primarily involve an examination of the proteinase-proteinase inhibitor balance within the lung, mechanisms by which this balance can be perturbed in favor of free enzyme, and the function of proteinase:proteinase inhibitor complexes in signalling for synthesis of acute phase proteins to offset this imbalance. In particular, the binding of both inhibitor:enzyme complexes and proteolytically inactivated inhibitors to specific receptors on cell surfaces will be followed to determine whether this induces cytokine synthesis and, indirectly, both protein synthesis and chemotaxis. Since the three-dimensional structure of the native form of inhibitors involved in the regulation of endogenous proteinases involved in tissue destruction is unknown (members of the Serpin family), it is also planned to complete the sequence and determine the crystal structure of one of these which has been isolated from equine leukocyte cytosol. In a separate study an investigation of the role of neutrophil proteinases in cell migration will also be carried out to determine whether such enzymes have alternate roles in addition to those involving the degradation of foreign or denatured proteins during phagocytosis. Finally, a study of the potential role of proteinases from pollens in lung disease will be initiated in order to determine whether such enzymes present in these gametes might be involved in the development of allergies or asthma.
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