The abundance of transforming growth factor-beta (TGF-beta) in normal airway epithelium suggests its participation in physiological processes to maintain airway homeostasis. The current study was designed to address the hypothesis that TGF-beta 1 and TGF-beta 2 might contribute to normal reparative response of airway epithelial cells (AECs). Treatments with exogenous TGF-beta 1 or TGF-beta 2 significantly enhanced wound repair of confluent AEC monolayers. Mechanical injury of AEC monolayers induced production of both TGF-beta 1 and TGF-beta 2. Wound repair of AECs was significantly reduced by a specific inhibitor of TGF-beta type I receptor kinase activity. We investigated whether the TGF-beta-enhanced repair required epidermal growth factor receptor (EGFR) transactivation and secretion of EGFR ligands. Both TGF-beta 1 and TGF-beta 2 enhanced EGFR phosphorylation and induced production of heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor-alpha (TGF-alpha) in AECs. Moreover, treatment with a broad-spectrum metalloproteinase inhibitor or anti-HB-EGF and anti-TGF-alpha antibodies inhibited the wound repair and the EGFR phosphorylation by TGF-beta 1 and TGF-beta 2, indicating that the TGF-beta 1 and TGF-beta 2 effects on wound repair required the release of HB-EGF and TGF-alpha. Our data, for the first time, have shown that both TGF-beta 1 and TGF-beta 2 play a stimulatory role in airway epithelial repair through EGFR phosphorylation following autocrine production of HB-EGF and TGF-alpha. These findings highlight an important collaborative mechanism between TGF-beta and EGFR in maintaining airway epithelial homeostasis. (C) 2011 Elsevier Inc. All rights reserved.