Obesity modulates the alveolar macrophage response

Introduction: Obesity, a rapidly worsening epidemic in the developed world, is associated with increased risk for the development of ARDS. Alveolar macrophages are key participants in the overexuberant pulmonary inflammatory response that characterizes ARDS. We hypothesize that alveolar macrophage function and phenotype are abnormally skewed by obesity. Methods: Macrophage and neutrophil counts as well as cytokine levels were determined in bronchoalveolar lavage (BAL) fluid from lean (10% fat) and diet-induced obese (60% fat) mice at baseline. Alveolar macrophages were isolated from uninjured obese and lean mice exposed to LPS in vitro for 4h after which cytokine levels were determined in culture supernatant. Next, wild-type mice received PKH26-PCL dye via o.p. instillation where after they were placed on 10% vs. 60% fat diet for 10 weeks and BAL cell populations were analyzed by flow cytometry. Results: Alveolar macrophage numbers and MCP-1 levels were found to be elevated in BAL of uninjured obese mice. Furthermore, alveolar macrophages from the uninjured obese mice showed an exaggerated in vitro cytokine response to LPS. The proportion of PKH26-PCL positive macrophages remaining in BAL after 10 weeks of diet was greater in the 10% fat (lean) diet-fed mice compared to that found in 60% fat diet-fed mice, suggesting that obesity induces monocyte/macrophage recruitment from the circulation to the lung over time. Conclusion: Our findings indicate that obesity increases monocyte/macrophage recruitment to the lung and that alveolar macrophage function and phenotype manifest an exaggerated pro-inflammatory state at baseline. These changes may drive the increased risk of developing ARDS that manifests in obese humans and mice.