Molecular aspects involved in leukocytes microbicidal and inflammatory activities in the lung

Abstract

The recognition of microorganisms by phagocytes involves complexes of receptors (PRRs) that recognize molecular patterns associated with pathogens (PAMPs), receptors for opsins (Fc gamma to C3b), toll type receptors, in addition to receptors for inflammatory mediators. Evidence exists of interactions between receptors of innate immunity, Fc gamma receptors and receptors for eicosanoids, and that these interactions influence the effector functions of the macrophages, such as phagocytosis and microbicide activity. These interactions can occur between the receptors present in lipidic rafts and/or G proteins involved which lead to induction via different transduction paths of signal elicited by the activation of these receptors. Recently, we demonstrated that leukotriene B4 increases the microbicide activity of alveolar macrophages infected with Klebsiella pneumoniae (opsonized with antibodies) and that this increase is dependent on the activation of PKC - delta and subsequent activation of the NADPH oxidase. It is not known, however, if the leukotrienes interfere with the formation of the phagolysosome, an important step in the control of infection by macrophages. Thus, the first part of this project aims to characterize the signaling paths activated in alveolar macrophages by activation of the Fc gamma receptors, toll type receptors and receptors for leukotrienes, individually or in association, and the consequences in phagocytosis, formation of phagosome and microbicide activity. In pulmonary inflammation the leukocytes that migrate to the lung are fundamental in the induction and resolution of the inflammatory process but they can also be important effectors of tissue lesion. As examples of inflammation mediated by leukocytes in the lung we have allergic asthma where the effector cells are the lymphocytes and eosinophils, pulmonary inflammation stemming from reperfusion after ischemia, in which the effector cell of the lesions is the neutrophil and pulmonary inflammation by LPS which represents a model of inflammation caused by activation of toll type receptors in macrophages. The activation of these cells so that they become effectors of lesion involves signaling through a vast range of receptors. Previous works in our laboratory showed that, in immunomediated inflammation, the pathological events depend on interactions involving receptors for prostaglandins, leukotrienes, PAF, bradykinin and endothelins. Thus, the second part of this project aims to determine the signaling paths activated in the course of allergic pulmonary inflammation (asthma) and non-allergic (LPS and pulmonary inflammation stemming from ischemia/reperfusion), the most relevant pathological events in each model (migration of eosinophils and T gamma/delta and NK T lymphocytes, bronchial hyperactivity, formation of mucous, endothelial lesion and tissue remodeling) and the effect of the lipidic mediators (prostaglandins, leukotrienes and PAF), IL17, bradikinin, endothelins, insulin and proteins related to cell stress (UPR, HO-1 and HSP70) in the signaling paths and in pathological events selected in each of the models. A better understanding of how these receptors function when in concert and of how the different signaling paths interfere some with the others, would permit us to develop new strategies for manipulating the functions of the leukocytes. This could lead to new forms of pharmacological intervention to increase natural immunity against pathogenetic microorganisms or inhibit the harmful effects of inflammation. (AU)