The anaphylatoxins, C3a and C5a, are low molecular polypeptides generated during activation of the complement cascade. Their potential for contributing to the pathogenesis of acute lung injury through activation of inflammatory cells and release of secondary mediators is well established. However, in the absence of specific C3a and C5a receptor antagonists, it is not possible to ascribe particular pathophysiological aspects of these disease situations to the anaphylatoxins per se, since there is an interplay of primary and secondary mediators and a multiplicity of potential target cells in juxtaposition in the lung. Further, virtually nothing is known of the role of these peptides in chronic lung diseases. We will study the potential for of these peptides in creating an animal model of chronic inflammatory lung disease. We propose to administer homologous species anaphylatoxins to guinea pigs by aerosol in sub-acute (ie., non-lethal) doses on a daily basis for a period of time to be determined, and monitor the effects physiologically, on baseline lung function and responsiveness to standard agonists, as well as biochemically, on levels of metalloendopeptidase, mucus, neuropeptides, and neuropeptide and anaphylatoxin receptors. The biology of the anaphylatoxins is dependent on their interaction with cellular receptors, and it is clear that we are presently unable to manipulate the latter variable in experimental systems. Thus another goal in our research is the development of reagents which will allow us to address the anaphylatoxin receptors independently of the anaphylatoxins. With these reagents in hand (ie., specially modified recombinant anaphylatoxins and cDNA probes and/or antibodies to their receptors), we will study the interaction of these peptides with particular lung cell types, including pulmonary vascular endothelial cells, airway and vascular smooth muscle cells, and sensory neurons, using in situ techniques as well as organ and/or cell cultures.
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