Editors' ChoiceLung Fibrosis

A fibrotic trio

Sci. Signal.  16 Feb 2016:
Vol. 9, Issue 415, pp. ec31
DOI: 10.1126/scisignal.aaf4595

Although the lung can regenerate after injury, repeated injury results in fibrosis, which compromises respiratory function. Cao et al. injected damaging chemicals into the tracheas of mice to investigate how fibrosis due to repetitive injury occurred. Mice receiving a single injection recovered blood oxygen concentration and exhibited re-epithelialization by type 1 alveolar cells and proliferation of the surfactant-producing type 2 alveolar epithelial cells. However, mice receiving repeated injections did not and, instead, had the sustained presence of protein markers of fibrosis (α-smooth muscle actin, collagen I, and hydroxyproline). Examination of Notch signaling, a regulator of lung fibroblasts, using transgenic Notch reporter mice revealed that Notch activation occurred in perivascular fibroblasts after repetitive injury. Repetitive lung injury resulted in an increase in the abundance of the Notch ligand Jagged1 (Jag1) in the pulmonary capillary endothelial cells (PCECs), which function not only as part of blood vessels but also as a source of paracrine signals in alveoli. Mice with an endothelial cell–specific knockout of Jag1 showed reduced fibrosis in response to repetitive lung injury, and fibroblasts in these mice showed reduced Notch activation (as detected using the reporter mice) and transforming growth factor–β (TGF-β) signaling (as assessed by binding of Smad3 to DNA). The chemokine receptor CXCR7 and its ligand CXCL12 (also known as SDF-1) are associated with endothelial cell–mediated tissue repair in other organs, and repeated injections reduced the abundance of this protective receptor in PCECs while increasing the amount of the CXCR7 ligand CXCL12. Administration of a CXCR7 agonist reduced lung damage and fibrosis in response to repeated injury, but not in animals with endothelial cell–specific knockout of CXCR7. However, lung endothelial cell–specific knockdown of Jag1 reduced markers of fibrosis in the CXCR7-deficient animals, suggesting that the increase in Jag1 may be at least partially a result of impaired CXCR7 signaling in PCECs. Indeed, a CXCR7 agonist reduced the Wnt-mediated increase in Jag1 abundance in cultured PCECs. Macrophages are a source of Wnt ligands, and depletion of these cells in mice reduced fibrosis in response to repetitive lung injury, but not in transgenic animals with endothelial cell–specific expression of a constitutively active form of β-catenin (the Wnt mediator responsible for stimulating Jag1 expression). Wnt3a was specifically induced in macrophages positive for vascular endothelial growth factor receptor 1 (VEGFR1), and these cells were recruited to the injured lungs. Knockout of Vegfr1 in these cells prevented the production of Wnt3a and the increase in Jag1 abundance in PCECs in response to repetitive lung injury. Compared with mice receiving wild-type macrophages, those that received Vegfr1-knockout macrophages showed reduced fibrosis, which was lost in mice with the constitutively active form of β-catenin in endothelial cells. Thus, long-term lung damage results in the recruitment of macrophages, which produce Wnt ligands that stimulate PCECs to increase the abundance of Jag1 that interacts with Notch on fibroblasts to promote fibrosis. Reduced signaling by protective CXCR7 in PCECs contributes to the increase in Jag1. Because CXCR7 agonists were beneficial in this mouse model, this arm of the pathway may be a useful target in patients as well.

Z. Cao, R. Lis, M. Ginsberg, D. Chavez, K. Shido, S. Y. Rabbany, G.-H. Fong, T. P. Sakmar, S. Rafii, B.-S. Ding, Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis. Nat. Med. 22, 154–162 (2016). [PubMed]