β1 Integrin regulates adult lung alveolar epithelial cell inflammation

Integrins, the extracellular matrix receptors that facilitate cell adhesion and migration, are necessary for organ morphogenesis; however, their role in maintaining adult tissue homeostasis is poorly understood. To define the functional importance of beta(1) integrin in adult mouse lung, we deleted it after completion of development in type 2 alveolar epithelial cells (AECs). Aged integrin-deficient mice exhibited chronic obstructive pulmonary disease-like (COPD-like) pathology characterized by emphysema, lymphoid aggregates. and increased macrophage infiltration. These histopathological abnormalities were preceded by beta(1) integrin-deficient AEC dysfunction such as excessive ROS production and upregulation of NF-kappa B-dependent chemokines, including CCL2. Genetic deletion of the CCL2 receptor, Ccr2, in mice with beta(1) integrin-deficient type 2 AECs impaired recruitment of monocyte-derived macrophages and resulted in accelerated inflammation and severe premature emphysematous destruction. The lungs exhibited reduced AEC efferocytosis and excessive numbers of inflamed type 2 AECs, demonstrating the requirement for recruited monocytes/macrophages in limiting lung injury and remodeling in the setting of a chronically inflamed epithelium. These studies support a critical role for beta(1) integrin in alveolar homeostasis in the adult lung.