Oxidized Phospholipids Derived from Apoptotic Pneumocytes Drives Macrophage Activation and Initiates Lung Fibrosis

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Project Summary Progressive lung fibrosis is a feature of systemic diseases and chronic injury but can also occur in the absence of any known etiology as with Idiopathic Pulmonary Fibrosis (IPF). IPF is a devastating disorder with a median survival of ~4 years from time of diagnosis and current medical therapy only modestly slows disease progression. Even fibrosis from known causes can lead to a difficult progressive course, thsu it is vital that the pathogenesis of fibrosis is more precisely elucidated in order to identify novel therapeutic targets. Recent studies from both human fibrotic diseases and animal models have identified a critical role for type II alveolar epithelial cell (AEC2) injury and apoptosis in the initiation of interstitial scarring. However, the downstream pathways that translate AEC2 injury/death into fibrosis remain undefined. Our preliminary data demonstrate that an array of AEC2 insults drives their expression of CCL2/CCL12, chemokines involved in pro-fibrotic monocyte/macrophage recruitment. The importance of this response was confirmed by demonstrating that mice deficient in AEC2-derived CCL12 developed attenuated fibrosis in a murine model. AEC2 injury can also progress to apoptosis with an accompanying oxidation of their abundant phospholipid stores, and we discovered that uptake and accumulation of oxidized phospholipid (oxPL) derived from apoptotic AEC2s (either released or retained within apoptotic bodies) induces a pro-fibrotic phenotypic switch in the ingesting lung macrophage. Administration of apoptotic AEC2s or oxPL into the lungs of uninjured mice is sufficient to drive lung fibrosis and this uptake is mediated by CD36. The accumulation of oxPL within macrophages is also determined by its catabolism which we have shown is regulated primarily by lysosomal phospholipase A2 (LPLA2). Our preliminary results indicate that the rapid intracellular degradation of oxPL by LPLA2 in alveolar macrophages can minimize macrophage activation. Compared to resident macrophages, monocyte-derived macrophages that are recruited to the injured lung exhibit a greater pro-fibrotic response to oxPL accumulation due to their decreases expression of LPLA2. These preliminary data motivate our central hypothesis that AEC2 injury/apoptosis results in a coordinated response in which the elaboration of CCL12 from injured AECs attracts monocyte-derived macrophages to the alveolar space where they engulf and accumulate oxPL resulting in robust pro-fibrotic activation. We will pursue a multifaceted approach using in vitro studies of primary murine and human macrophages with in vivo mouse experiments using novel transgenic mice, bone marrow transplant chimeras, and complementary models of lung fibrosis. We have formed a synergistic team with expertise in lipids, monocyte/macrophages, and AEC2s. Our research project specifically addresses a recognized knowledge gap in fibrosis pathogenesis. Importantly, the results of these studies will define previously unexplored mechanisms that critically regulate fibrosis and will inform the development of novel therapies.