TY - JOUR T1 - Interdependence of HIF1α /TGFβ1 activity in induction of pulmonary fibrosis JF - European Respiratory Journal JO - Eur Respir J VL - 42 IS - Suppl 57 SP - P516 AU - Chandru Hanumegowda AU - Kjetil Ask AU - Jack Gauldie AU - Martin Kolb Y1 - 2013/09/01 UR - http://erj.ersjournals.com/content/42/Suppl_57/P516.abstract N2 - Introduction:Pulmonary Fibrosis is a chronic lung disease likely involving multiple microinjuries to alveolar epithelium, resulting in excess deposition of extracellular matrix (ECM) and hardening/stiffening of tissue. Transforming growth factor β1 (TGFβ1) is a key regulator of ECM expression and is linked with the development of pulmonary fibrosis. Activation of Hypoxia inducible factor-1a (HIF1α) under hypoxic conditions in fibrotic lung is expected and could promote perpetuation of the disease.Objective:Evaluate if concomitant overexpression of HIF1α / TGFβ1 worsens or improves pulmonary fibrosis.Methods:Adenoviral vectors each 6 X 108 pfu of AdHIF1α /AdDL-70 (control), AdTGFβ1/AdDL-70 and AdHIF1α /AdTGFβ1 or AdDL70/AdDL70 in combination were administered intratracheally to rats. Lung extracts ELISA, western blot, RT-PCR, collagen assay and lung histopathology, elastance measures and HIF1α DNA binding assays were carried out to assess tissue fibrosis.Results:Concomitant administration of AdHIF1α/AdTGFβ1 enhances the fibrotic response. TGFβ1 is able to induce fibrosis with induction of HIF1α. Over expression of HIF1α alone induces limited fibrosis but enhances the ability of TGFβ1 to further develop sustained fibrosis. This study highlights a crucial role of TGFβ1 in mediating the effect of HIF1α and vice versa.Conclusion:Combined activation of HIF1α/TGF β1 in lungs enhances inflammation, marked distortion of lung structure, over expression of smooth muscle actin and plasminogen activator inhibitor-1, accumulation of collagen and increases lung elastance, indicating that HIF1α activation may therefore have a role in progression of chronic fibrotic diseases such as IPF. ER -