Heterotrimeric guanine nucleotide–binding protein (G protein) signaling links hundreds of G
protein–coupled receptors (GPCRs) with four G protein signaling pathways. Two of these,
one mediated by Gq and G11 (Gq/11) and the other by G12 and G13 (G12/13), are implicated in
the force-dependent activation of transforming growth factor–β (TGFβ) in lung epithelial
cells. Reduced TGFβ activation in alveolar cells leads to emphysema, whereas enhanced
TGFβ activation promotes acute lung injury and idiopathic pulmonary fibrosis. Therefore,
precise control of alveolar TGFβ activation is essential for alveolar homeostasis. Here, we
investigated the involvement of the Gq/11and G12/13 pathways in epithelial cells in generating
active TGFβ and regulating alveolar inflammation. Mice deficient in both Gαq and Gα11
developed inflammation that was primarily caused by alternatively activated (M2-polarized)
macrophages, enhanced matrix metalloprotease 12 (MMP12) production, and age-related
alveolar airspace enlargement consistent with emphysema. Mice with impaired Gq/11
signaling had reduced stretch-mediated generation of TGFβ by epithelial cells and enhanced
macrophage MMP12 synthesis, but were protected from the effects of ventilator-induced lung
injury. Furthermore, synthesis of the cytokine interleukin-33 (IL-33) was increased in these
alveolar epithelial cells, resulting in the M2-type polarization of alveolar macrophages independently of the effect on TGFβ. Our results suggest that alveolar Gq/11 signaling
maintains alveolar homeostasis, and likely independently increases TGFβ activation in
response to mechanical stress of the epithelium and decreases epithelial IL-33 synthesis.
Together, these findings suggest that disruption of Gq/11 signaling promotes inflammatory
emphysema but protects against mechanically induced lung injury.