Mechanisms of pulmonary inflammation will be studied using an experimental animal model. In previous work, we have shown that cell activators (e.g., Con A, PHA, LPS) are usually toxic when inhaled, producing interstitial pulmonary inflammation directly and, in some cases, also triggering immune complex reactions between inhaled antigen and humoral antibody. Cell activators (CAs) readily activate macrophages to release various mediators, and these mediators (including reactive oxygen intermediates and monokines) are known to effect many aspects of the inflammatory response. Recently, we have shown that alveolar macrophage function is modulated by discrete serum constituents. This proposal addresses the central role of the alveolar macrophage in response to stimulation by CAs, and how these responses are regulated by serum factors. First, we will purify and physicochemically characterize two serum factors which """"""""condition"""""""" AM, thereby enhancing their responsiveness to CA activation. Second, we will define the mechanism of action of these factors, including an analysis of their binding to AM cell membranes, their effect on membrane NADPH oxidase activity, their effect on interleukin 1 (IL-1) and tumor necrosis factor (TNF) production, and also Ia and transferrin receptor expression. In addition, we will relate serum conditioning of AM to proto-oncogene expression. In addition, we will relate serum conditioning of AM to proto-oncogene expression and protein kinase C translocation in these cells. Third, we will study the effects of serum conditioning factors in vivo as follows: 1) do these factors, when administered as an aerosol to rabbits, effect an up-regulation of AM function in vivo?; 2) do chemically-induced increases in lung microvascular permeability also lead to enhanced AM function in vivo?; 2) do chemically-induced increases in lung microvascular permeability also lead to enhanced AM function in vivo, and can serum conditioning factor activity be identified in the lavage fluid?; and 3) are the usually pathogenic effects of inhaled CA's associated with the release of serum conditioning factors into the pulmonary air spaces, in association with an up-regulation of AM secretory activity? These studies will further define mechanisms of inflammatory lung disease, outlining both the mechanisms which normally protect the lung against inflammatory injury, together with those """"""""windows of vulnerability"""""""" through which the protective mechanisms may be circumvented. In addition, these studies address means for enhancing AM function in vivo, since this may prove of significant therapeutic benefit in protecting immunocompromised individuals against opportunistic pulmonary infections.
| Lamb Jr, L S; Willoughby, J B; Willoughby, W F (1995) Morphologic and functional characteristics of alveolar macrophages following cryopreservation. Cryobiology 32:344-57 |
| Gerberick, G F; Jaffe, H A; Willoughby, J B et al. (1986) Relationships between pulmonary inflammation, plasma transudation, and oxygen metabolite secretion by alveolar macrophages. J Immunol 137:114-21 |
| Gerberick, G F; Willoughby, J B; Willoughby, W F (1985) Serum factor requirement for reactive oxygen intermediate release by rabbit alveolar macrophages. J Exp Med 161:392-408 |
| Willoughby, W F; Willoughby, J B; Gerberick, G F (1985) Polyclonal activators in pulmonary immune disease. Clin Rev Allergy 3:197-216 |
