• Shaney L Barratt, Thomas Blythe, Caroline Jarrett, Khadija Ourradi, Golda Shelley-Fraser, Michael J Day, Yan Qiu, Steve Harper, Toby M Maher, Sebastian Oltean, Thomas J Hames, Chris J Scotton, Gavin I Welsh, David O Bates, and Ann B Millar.
• 1 Academic Respiratory Unit, School of Clinical Sciences.
• Am. J. Respir. Crit. Care Med. 2017 Aug 15; 196 (4): 479-493.

RationaleFibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-A165a and VEGF-A165b, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF.ObjectivesTo establish VEGF-A isoform expression and functional effects in IPF.MethodsWe used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTA+/-TetoCre+/-LoxP-VEGF-A+/+ to conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice.Measurements And Main ResultsIPF and normal lung fibroblasts differentially expressed and responded to VEGF-A165a and VEGF-A165b in terms of proliferation and matrix expression. Increased VEGF-A165b was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-A165b inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-A165b to wild-type mice.ConclusionsThese results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-Axxxa to VEGF-Axxxb, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair.

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