{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:15:52Z","timestamp":1791278152593,"version":"4.1.0"},"reference-count":63,"publisher":"American Physiological Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2014,4,15]]},"abstract":"<jats:p> A number of growth factors and signaling pathways regulate matrix deposition and fibroblast proliferation in the lung. The epidermal growth factor receptor (EGFR) family of receptors and the transforming growth factor-\u03b2 (TGF-\u03b2) family are active in diverse biological processes and are central mediators in the initiation and maintenance of fibrosis in many diseases. Transforming growth factor-\u03b1 (TGF-\u03b1) is a ligand for the EGFR, and doxycycline (Dox)-inducible transgenic mice conditionally expressing TGF-\u03b1 specifically in the lung epithelium develop progressive fibrosis accompanied with cachexia, changes in lung mechanics, and marked pleural thickening. Although recent studies demonstrate that EGFR activation modulates the fibroproliferative effects involved in the pathogenesis of TGF-\u03b2 induced pulmonary fibrosis, in converse, the direct role of EGFR induction of the TGF-\u03b2 pathway in the lung is unknown. The \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>6<\/jats:sub> integrin is an important in vivo activator of TGF-\u03b2 activation in the lung. Immunohistochemical analysis of \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>6<\/jats:sub> protein expression and bronchoalveolar analysis of TGF-\u03b2 pathway signaling indicates activation of the \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>6<\/jats:sub>\/TGF-\u03b2 pathway only at later time points after lung fibrosis was already established in the TGF-\u03b1 model. To determine the contribution of the \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>6<\/jats:sub>\/TGF-\u03b2 pathway on the progression of established fibrotic disease, TGF-\u03b1 transgenic mice were administered Dox for 4 wk, which leads to extensive fibrosis; these mice were then treated with a function-blocking anti-\u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>6<\/jats:sub> antibody with continued administration of Dox for an additional 4 wk. Compared with TGF-\u03b1 transgenic mice treated with control antibody, \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>6<\/jats:sub> inhibition significantly attenuated pleural thickening and altered the decline in lung mechanics. To test the effects of genetic loss of the \u03b2<jats:sub>6<\/jats:sub> integrin, TGF-\u03b1 transgenic mice were mated with \u03b2<jats:sub>6<\/jats:sub>-null mice and the degree of fibrosis was compared in adult mice following 8 wk of Dox administration. Genetic ablation of the \u03b2<jats:sub>6<\/jats:sub> integrin attenuated histological and physiological changes in the lungs of TGF-\u03b1 transgenic mice although a significant degree of fibrosis still developed. In summary, inhibition of the \u03b2<jats:sub>6<\/jats:sub> integrin led to a modest, albeit significant, effect on pleural thickening and lung function decline observed with TGF-\u03b1-induced pulmonary fibrosis. These data support activation of the \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>6<\/jats:sub>\/TGF-\u03b2 pathway as a secondary effect contributing to TGF-\u03b1-induced pleural fibrosis and suggest a complex contribution of multiple mediators to the maintenance of progressive fibrosis in the lung. <\/jats:p>","DOI":"10.1152\/ajplung.00357.2013","type":"journal-article","created":{"date-parts":[[2014,2,8]],"date-time":"2014-02-08T06:50:32Z","timestamp":1391842232000},"page":"L726-L735","source":"Crossref","is-referenced-by-count":53,"title":["Inhibition of the \u03b1<sub>v<\/sub>\u03b2<sub>6<\/sub> integrin leads to limited alteration of TGF-\u03b1-induced pulmonary fibrosis"],"prefix":"10.1152","volume":"306","author":[{"given":"Satish K.","family":"Madala","sequence":"first","affiliation":[{"name":"Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas 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