Influence of the lung microbiome on macrophage responses to lung damage

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Abstract Aspiration of gastric acid into the lower respiratory tract can lead to pneumonitis, pneumonia, acute lung injury (ALI), and even the more severe ARDS. We propose that the ability to survive a given disease is determined by two main factors, resistance (the ability to ameliorate the root cause of a disease) and tolerance (the ability to cope with the effects the disease). Many innate immune cell types play roles in tissue repair responses. Macrophages polarize into several subtypes with different functions. The largest categories are known as M1 (important in response to infection) and M2 (important in tissue repair and anti-inflammatory). Our data show that at steady-state aveolar macrophages, the tissue resident macrophages of the lung, are polarized towards the M2 pheonotype. Our preliminary data show that acid aspiration induced ALI has a similar impact as infection, inducing an M1 phenotype. Collectively these data suggest that both severe infection and inflammation alter the programming of macrophages, and decrease their ability to induce the repair phenotype. Recent studies have shown that an individual's intestinal microbiome influences the response to many diseases. However, the impact of the lung microbiome has not been fully explored, in part because only recently have people realized that there is a complex microbiome in the lung. Human studies demonstrate correlation between lung diseases and alterations of the airway microbiome, however there is a lack of direct evidence for causation. To examine this have developed a mouse model, where we can directly alter the lung microbiome. Our preliminary data demonstrate that the mouse lung, as is seen in many human lung diseases, has decreased microbial diversity during inflammation. In preliminary studies we have demonstrated that interaction with microbes commonly found in the pulmonary system influences the development of macrophages. Our long-term goal is to manipulate the airway microbiome to increase tolerance to lung disease. The overall objective of this proposal is to determine how damage-induced changes to the lung microbiome alter macrophage responses that are important in disease tolerance. Our data has allowed us to formulate the hypothesis that damage-induced changes in the lung microbiome decrease disease tolerance by altering the function of macrophages. To explore this hypothesis, we will determine how the airway microbiome is altered after lung damage (Aim 1), how exposure to specific airway microbes affect the function and development of macrophages (Aim 2), and how microbiota-induced changes to pulmonary macrophages influence host disease tolerance responses (Aim 3). This study will fundamentally alter our understanding of the influence of the lung microbiome on the ability of the innate immune response to increase tolerance of lung damage.