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(American Journal of Pathology. 2003;163:533-542.)
© 2003 American Society for Investigative Pathology

Integrin vß8-Mediated Activation of Transforming Growth Factor-ß Inhibits Human Airway Epithelial Proliferation in Intact Bronchial Tissue

Lars Fjellbirkeland^*, Stephanie Cambier^*, V. Courtney Broaddus, Arthur Hill, Paul Brunetta, Gregory Dolganov, David Jablons and Stephen L. Nishimura^*

From the Department of Anatomic Pathology and Lung Biology Center,^* San Francisco General Hospital, University of California at San Francisco/Mt. Zion Cancer Center and the Department of Medicine, Pulmonary Division, and the Department of Surgery, University of California at San Francisco, San Francisco, California

Transforming growth factor (TGF)-ß is a potent multifunctional cytokine that is an essential regulator of epithelial proliferation. Because TGF-ß is expressed almost entirely in a latent state in vivo, a major source of regulation of TGF-ß function is its activation. A subset of integrins, vß8 and vß6, which are expressed in the human airway, has recently been shown to activate latent TGF-ß in vitro, suggesting a regulatory role for integrins in TGF-ß function in vivo. Here we have developed a novel, biologically relevant experimental model of human airway epithelium using intact human bronchial tissue. We have used this model to determine the function of integrin-mediated activation of TGF-ß in the airway. In human bronchial fragments cultured in vitro, authentic epithelial-stromal interactions were maintained and integrin and TGF-ß expression profiles correlated with profiles found in normal lung. In addition, in this model, we found that either the integrin vß8 or TGF-ß could inhibit airway epithelial cell proliferation. Furthermore, we found that one mechanism of integrin-vß8-dependent inhibition of cell proliferation was through activation of TGF-ß because anti-ß8 antibody blocked the majority (76%) of active TGF-ß released from bronchial fragments. These data provide compelling evidence for a functional role for integrin-mediated activation of TGF-ß in control of human airway epithelial proliferation in vivo.

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