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1 Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: cwaters{at}physio1.utmem.edu.
Repair of the airway epithelium after injury is critical for restoring normal lung function and maintaining barrier function. The re-epithelialization process involves spreading and migration of the cells into the denuded area followed later by cell proliferation. Rho GTPases are key components of the wound healing process in many different types of tissues, but the specific roles for RhoA and Rac1 vary and have not been identified in lung epithelial cells. We investigated whether RhoA and Rac1 regulate wound closure of bronchial epithelial cells. RhoA and Rac1 proteins were efficiently expressed in a cell line of human bronchial epithelial cells (16HBE) by adenovirus-based gene transfer. We found that both constitutively active RhoA and dominant negative RhoA inhibited wound healing suggesting that both activation and inhibition of RhoA interfere with normal wound healing. Over-expression of wild type Rac1 induced upregulation of RhoA, disrupted intercellular junctions, and inhibited wound closure. Dominant negative Rac1 also inhibited wound closure. Inhibition of the downstream effector of RhoA, Rho-kinase (ROCK), with Y-27632 suppressed actin stress fibers and focal adhesion formation, increased Rac1 activity, and stimulated wound closure. The activity of both RhoA and Rac1 are influenced by the polymerization state of microtubules, and cell migration involves coordinated action of actin and microtubules. Microtubule depolymerization upon nocodazole treatment led to an increase in focal adhesions and decreased wound closure. Moreover pretreatment with nocodazole followed by washout led to microtubule growth in the membrane ruffles at the cell periphery with reduced focal adhesions. We conclude that coordination of both RhoA and Rac1 activity contribute to bronchial epithelial wound repair mechanisms in vitro, that inhibition of Rho kinase accelerates wound closure, and that efficient repair involves intact microtubules.
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