{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T22:06:59Z","timestamp":1788041219089,"version":"build-2784847793"},"reference-count":40,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2015,2,1]]},"abstract":"<jats:p> Hypothyroidism may reduce, whereas hyperthyroidism may aggravate, asthma symptoms. The mechanisms underlying this relationship are largely unknown. Since thyroid hormones have central roles in cell growth and differentiation, we hypothesized that airway remodeling, in particular increased airway smooth muscle (ASM) mass, may be involved. To address this hypothesis, we investigated the effects of triiodothyronine (T<jats:sub>3<\/jats:sub>) and l-thyroxine (T<jats:sub>4<\/jats:sub>) in the absence and presence of the profibrotic transforming growth factor (TGF)-\u03b21 on human ASM cell phenotype switching. T<jats:sub>3<\/jats:sub> (1\u2013100 nM) and T<jats:sub>4<\/jats:sub> (1\u2013100 nM) did not affect basal ASM proliferation. However, when combined with TGF-\u03b21 (2 ng\/ml), T<jats:sub>4<\/jats:sub> synergistically increased the proliferative response, whereas only a minor effect was observed for T<jats:sub>3<\/jats:sub>. In line with a switch from a contractile to a proliferative ASM phenotype, T<jats:sub>4<\/jats:sub> reduced the TGF-\u03b21-induced contractile protein expression by \u223c50%. Cotreatment with T<jats:sub>3<\/jats:sub> reduced TGF-\u03b21-induced contractile protein expression by \u223c25%. The synergistic increase in proliferation was almost fully inhibited by the integrin \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>3<\/jats:sub> antagonist tetrac (100 nM), whereas no significant effects of the thyroid receptor antagonist 1\u2013850 (3 \u03bcM) were observed. Inhibition of MEK1\/2, downstream of the integrin \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>3<\/jats:sub>, also inhibited the T<jats:sub>4<\/jats:sub>- and TGF-\u03b21-induced proliferative responses. Collectively, the results indicate that T<jats:sub>4<\/jats:sub>, and to a lesser extent T<jats:sub>3<\/jats:sub>, promotes a proliferative ASM phenotype in the presence of TGF-\u03b21, which is predominantly mediated by the membrane-bound T<jats:sub>4<\/jats:sub> receptor \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>3<\/jats:sub>. These results indicate that thyroid hormones may enhance ASM remodeling in asthma, which could be of relevance for hyperthyroid patients with this disease. <\/jats:p>","DOI":"10.1152\/ajplung.00071.2014","type":"journal-article","created":{"date-parts":[[2014,12,6]],"date-time":"2014-12-06T00:39:12Z","timestamp":1417826352000},"page":"L301-L306","source":"Crossref","is-referenced-by-count":23,"title":["<scp>l<\/scp>-Thyroxine promotes a proliferative airway smooth muscle phenotype in the presence of TGF-\u03b21"],"prefix":"10.1152","volume":"308","author":[{"given":"Bart G. 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