ELUCIDATING THE FUNCTION AND DYNAMICS OF RESIDENT AND RECRUITED MACROPHAGE POPULATIONS IN THE LUNG
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Acute lung injury and chronic lung inflammation are major causes of morbidity and mortality in the US and worldwide. The cellular and molecular factors that function to limit the extent of acute and chronic inflammation in order to preserve the physiological roles of the lungs have not been fully defined. Here we use two sources of pulmonary inflammation – severe malaria infection resulting in acute lung injury and elastase-induced lung damage leading to chronic emphysema – to investigate the mechanisms that govern the nature and extent of lung injury. Employing the P. berghei-C57BL/6 mouse model, we demonstrate that sequestration of infected erythrocytes on post-capillary endothelial surfaces results in lung injury and the rapid recruitment of inflammatory monocytes from the circulation; which were instrumental in phagocytic clearance of adherent parasitized cells. However, in contrast, alveolar macrophages did not contribute to clearance of malaria-infected cells. Infection of CCR2-/- animals, which exhibited impaired monocyte recruitment and parasite clearance, resulted in elevated parasite burden and exacerbated lung injury. Results from CD36-/- and CD36 bone marrow chimeric mice demonstrated that parasite sequestration in the absence of CD36-mediated phagocytic clearance by monocytes results in exaggerated lung pathology. Hence, the data suggest a model in which the level of malaria-induced lung pathology is proportional to steady-state levels of parasite adherence and monocyte-driven phagocytic clearance. Employing the elastase mouse model of emphysema, we demonstrated that, unlike the malaria system, lung-resident alveolar macrophages, not recruited monocytes, play a dominant role in the inflammatory response. Upon elastase-induced lung damage, alveolar macrophages proliferated and dynamically changed their morphology, surface phenotype, gene expression profile and adopted a mixed M1/M2 activation phenotype. These results suggest upon initial tissue damage, resident alveolar macrophages could contribute significantly to the regulation of progressive emphysematous lung injury. These two studies have clarified our understanding of the dynamic properties and functional roles that resident alveolar macrophages and recruited monocyte-derived macrophages adopt to regulate the degree of acute and chronic pulmonary inflammation. Thus, these studies may contribute toward the development of future therapeutic approaches protecting from severe inflammatory lung diseases.