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Published ahead of print on May 18, 2006, doi:10.1165/rcmb.2006-0121OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 4, October 2006, 466-473

A more recent version of this article appeared on October 1, 2006
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Submitted on March 23, 2006
Revised on May 15, 2006

Activation of Alveolar Macrophages via the Alternative Pathway in Herpesvirus-induced Lung Fibrosis

Ana L Mora1*, Edilson Torres-Gonzalez2, Mauricio Rojas1, Claudia Corredor2, Jeffrey Ritzenthaler2, Jianguo Xu2, Jesse Roman3, Kenneth Brigham1, and Arlene Stecenko4

1 CTL, Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Emory University, Atlanta, GA, USA; McKelvey Lung Transplantation Center, Emory University, Atlanta, GA, USA, 2 CTL, Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Emory University, Atlanta, GA, USA, 3 CTL, Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Emory University, Atlanta, GA, USA; Atlanta VA Medical Center, Atlanta, GA, USA, 4 CTL, Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Emory University, Atlanta, GA, USA; McKelvey Lung Transplantation Center, Emory University, Atlanta, GA, USA; Division of Pulmonary, Allergy, Cystic Fibrosis and Sleep Department of Pediatrics, Emory University, Atlanta, GA, USA

* To whom correspondence should be addressed. E-mail: amora{at}emory.edu.

The etiology of Idiopathic Pulmonary Fibrosis (IPF) is unknown. Because viral pathogenesis of IPF has been suggested, we have established a murine model of progressive pulmonary fibrosis by infecting IFN{gamma}R deficient mice (IFN{gamma}R-/-) with the murine gammaherpesvirus 68 (MHV68). Since alveolar macrophages in humans with IPF have been implicated in driving the pro-fibrotic response, we studied their role in our model. Chronic herpesvirus infection of the lung was associated with recruitment of alveolar macrophages to areas with epithelial hyperplasia and fibrosis in infected lungs. Using immunohistochemistry, western blot and RT-PCR techniques, we demonstrated that recruited alveolar macrophages showed high levels of expression of Ym1/2, FIZZ1, IGF1, and Arginase I and also active transcription of fibronectin, indicative of activation of macrophages by an alternative pathway. Arginase I expression was also evident in interstitial fibroblasts and increased arginase activity was found in lungs of infected animals. Lung tissue from patients with IPF showed increased expression of Arginase I in epithelial cells, fibroblast foci and alveolar macrophages compared to normal lung. These results suggest that virus induced upregulation of Arginase I could be a mechanism driving lung fibrogenesis.






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