A combination of alveolar type 2-specific p38α activation with a high-fat diet increases inflammatory markers in mouse lungs.

Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease afflict millions of individuals globally and are significant sources of disease mortality. While the molecular mechanisms underlying such diseases are unclear, environmental and social factors, such as cigarette smoke and obesity, increase the risk of disease development. Yet, not all smokers or obese individuals will develop chronic respiratory diseases. The mitogen-activated protein kinase p38α is abnormally active in such maladies, but its contribution, if any, to disease etiology is unknown. To assess whether p38α activation per se in the lung could impose disease symptoms, we generated a transgenic mouse model allowing controllable expression of an intrinsically active variant, p38α(D176A+F327S), specifically in lung alveolar type 2 pneumocytes. Sustained expression of p38α(D176A+F327S) did not appear to induce obvious pathological outcomes or to exacerbate inflammatory outcomes in mice challenged with common respiratory disease triggers. However, mice expressing p38α(D176A+F327S) in alveolar type 2 cells and fed with a high-fat diet exhibited increased numbers of airway eosinophils and lymphocytes, upregulated levels of proinflammatory cytokines and chemokines including interleukin-1β and eotaxin, as well as a reduction in levels of leptin and adiponectin within the lung. Neither high-fat diet nor p38α(D176A+F327S) alone induced such outcomes. Perhaps in obese individuals with associated respiratory diseases, elevated p38α activity which happens to occur is the factor that promotes their development.