This overall objective of this proposal is the preparation of the Principal Investigator for a successful career as an independent clinician scientist. The proposal outlines a training program as well as mentored laboratory research which will provide broad exposure to pulmonary cell biology and mechanisms of innate immunity. The Sponsor, Jo Rae Wright PhD, is an eminent scientist and educator with expertise in surfactant biology, host defense of the lung, and innate immune mechanisms. This project will advance an important but incompletely understood aspect of lung biology, the mechanisms controlling the resolution of inflammation within the alveolar airspace. Specifically, this work will focus on the role of Surfactant Protein A, a major alveolar protein, in promoting the resolution of alveolar inflammation through its effects on alveolar macrophages and apoptotic neutrophils. The recognition and phagocytosis of apoptotic cells is a rapid, non-inflammatory clearance mechanism and a vital component of inflammation resolution in the lung. Infiltrating neutrophils (PMNs) undergo apoptosis and, subsequent, clearance after an inflammatory insult to the lung. The hypothesis to be tested in this proposal is that SP-A promotes the resolution of inflammation in the alveolar space by stimulating alveolar macrophages (AMs) to phagocytose apoptotic PMNs and to release anti-inflammatory cytokines. Using a rat model of endotoxin (LPS)-induced acute lung injury, this work will analyze the interactions of AMs with apoptotic cells, before and after varying periods of LPS injury, in the absence or presence of SP-A.
Specific aims i nclude: 1) Define how LPS-induced lung injury alters AM function, 2) Determine SP-A's effect on AM phagocytosis of apoptotic cells after LPS injury, 3) Identify the molecular interactions of SP-A with apoptotic cells and with AMs, and 4) Define SP-A's effect on cytokine production associated with the phagocytosis of apoptotic cells by AMs. This work will yield new insight into the mechanisms regulating the role of the innate immune system (SP-A and AMs) in resolving inflammation within the alveolar space.