Type 2 alveolar epithelial cells (AEC2s) secrete pulmonary surfactant, undergo long-term self-renewal and generate type 1 AECs, which mediate the gas exchange. In Nature Medicine, Noble and colleagues show that expression of the innate immunoreceptor TLR4 and the extracellular matrix component hyaluronan (HA) on AEC2s is important for their renewal and lung repair after injury. In mice, TLR4 expression increases in the lung after injury, and Tlr4−/− mice are more susceptible to injury and have an enhanced fibrotic response relative to that of wild-type mice. TLR4- and HA-deficient AEC2s proliferate less and have lower colony-forming potential in organoid cultures than do wild-type AEC2s. TLR4- and HA-deficient mice have lower IL-6 expression in the lungs, and recombinant IL-6 increases AEC2 proliferation, lung generation and survival after injury. AEC2s from patients with pulmonary fibrosis have lower colony-forming efficiency and HA expression than do those from healthy donors, whereas their TLR4 expression is normal.

Nat. Med. (3 October 2016) doi:10.1038/nm.4192