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* From Vancouver Hospital (Dr. Khalil), University of British Columbia, Vancouver, BC; the BC Cancer Agency (Dr. O’Connor), Vancouver, BC; the NYU Medical Center (Drs. Gold and Parekh), New York, NY; and the University of Washington (Dr. Raghu), Seattle, WA.
Correspondence to: Nasreen Khalil, MD, FCCP, 655 West 12th Ave, Vancouver, BC, V5Z 4R4 Canada; e-mail: nasreen.khalil{at}bccdc.hnet.bc.ca
Transforming growth factor (TGF)-ß1 has been demonstrated to be important in the pathogenesis of animal models of pulmonary fibrosis and in human fibrotic lung diseases.1 TGF-ß1 is usually released in a biologically inactive form because of its noncovalent association with the latency-associated peptide-1.2 Using immunohistochemistry, alveolar macrophages (AMs) and epithelial cells lining honeycomb cysts in lung sections with idiopathic pulmonary fibrosis (IPF) express latent TGF-ß1.3 To be biologically effective, the latency-associated peptide-1 must be removed from its association with TGF-ß1.2 Therefore, it was next determined if AMs and epithelial cells lining honeycomb cysts release biologically active TGF-ß1. Five patients with the clinical diagnosis of IPF and five patients with no inflammation or fibrosis were used as control subjects. BAL was performed on IPF patients at two sites that included areas with honeycomb cysts and lung that appeared apparently normal as detected by high-resolution computed axial tomography. AMs of IPF patients from both sites but not those from normal control subjects released active TGF-ß1. Furthermore, in IPF patients, the BAL fluid from an area of honeycomb lung compared to an area with no apparent changes contained increased quantities of active TGF-ß1. BAL fluid from normal control subjects contained only latent TGF-ß. For a biological response to occur, the active TGF-ß1 must interact with both of its receptors, TGF-ß receptor (TßR)-I and TßR-II.4 The distribution of TßR-II by immunohistochemistry was ubiquitous in normal and IPF lungs. However, TßR-I expression was markedly reduced on all cells in areas of honeycomb cysts, especially hyperplastic type 2 alveolar epithelial cells (AECs). In contrast, there was expression of TßR-I on AECs that had a type 1 morphology and interstitial fibroblasts. TGF-ß1 is a potent inhibitor of epithelial cell proliferation,4 and the loss of TßR-I on hyperplastic type 2 AECs may be important in rendering these cells resistant to the antiproliferative effects of the TGF-ß1 present in honeycomb cysts. This property may be important for regeneration of injured epithelium by proliferation. The presence of TßR-I on AECs would be important for cessation of continued proliferation and induction of differentiation. Since fibroblasts express both TßRs, they are likely to respond to TGF-ß1 by proliferation and connective tissue synthesis. In conclusion, these results provide evidence for cell type-specific regulation of TGF-ß1 function in vivo and suggest that several mechanisms controlling the effects of TGF-ß1 are likely to be involved in the pathogenesis of IPF.
Footnotes
Abbreviations: AEC = alveolar epithelial cell; AM = alveolar macrophage; IPF = idiopathic pulmonary fibrosis; TßR = transforming growth factor-ß1 receptor; TGF = transforming growth factor
This work was supported by the Medical Research Council of Canada.
References
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