Lung infection with γ-herpesvirus induces progressive pulmonary fibrosis in Th2-biased mice

被引:82
作者
Mora, AL
Woods, CR
Garcia, A
Xu, JG
Rojas, M
Speck, SH
Roman, J
Brigham, KL
Stecenko, AA
机构
[1] Emory Univ, Div Pulm Allergy & Crit Care, Dept Med, Atlanta, GA 30322 USA
[2] Emory Univ, Ctr Translat Res Lung, Atlanta, GA 30322 USA
[3] Emory Univ, McKelvey Lung Transplantat Ctr, Div Pathol, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA
[4] Emory Univ, McKelvey Lung Transplantat Ctr, Div Microbiol & Immunol, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA
关键词
interstitial lung diseases; virus diseases; animal disease model; T helper 2;
D O I
10.1152/ajplung.00007.2005
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Idiopathic pulmonary fibrosis ( IPF) is a progressive, fibrotic lung disease of unknown etiology. A viral pathogenesis in IPF has been suggested since > 95% of IPF patients have evidence of chronic pulmonary infection with one or more herpesviruses. To determine whether pulmonary infection with herpesvirus can cause lung fibrosis, we infected mice with the murine gamma-herpesvirus 68 ( MHV68). Because IPF patients have a T helper type 2 ( Th2) pulmonary phenotype, we used IFN-gamma R-/-, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-gamma R-/- mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in IPF, increased transforming growth factor-beta expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase- 7, were also present in chronically infected IFN-gamma R-/- mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial IPF. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus pulmonary infection in IFN-gamma R-/- mice causes progressive pulmonary fibrosis and many of the pathological features seen in IPF.
引用
收藏
页码:L711 / L721
页数:11
相关论文
共 47 条
[1]  
[Anonymous], 2000, AM J RESP CRIT CARE, V161, P646, DOI DOI 10.1164/AJRCCM.161.2.ATS3-00
[2]   Effect of lack of interleukin-4, interleukin-12, interleukin-18, or the interferon-γ receptor on virus replication, cytokine response, and lung pathology during respiratory syncytial virus infection in mice [J].
Boelen, A ;
Kwakkel, J ;
Barends, M ;
de Rond, L ;
Dormans, J ;
Kimman, T .
JOURNAL OF MEDICAL VIROLOGY, 2002, 66 (04) :552-560
[3]   Attenuation of lung inflammation and fibrosis in interferon-γ-deficient mice after intratracheal bleomycin [J].
Chen, ES ;
Greenlee, BM ;
Wills-Karp, M ;
Moller, DR .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2001, 24 (05) :545-555
[4]   Specific history of heterologous virus infections determines anti-viral immunity and immunopathology in the lung [J].
Chen, HD ;
Fraire, AE ;
Joris, I ;
Welsh, RM ;
Selin, LK .
AMERICAN JOURNAL OF PATHOLOGY, 2003, 163 (04) :1341-1355
[5]   Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis [J].
Chilosi, M ;
Poletti, V ;
Zamò, A ;
Lestani, M ;
Montagna, L ;
Piccoli, P ;
Pedron, S ;
Bertaso, M ;
Scarpa, A ;
Murer, B ;
Cancellieri, A ;
Maestro, R ;
Semenzato, G ;
Doglioni, C .
AMERICAN JOURNAL OF PATHOLOGY, 2003, 162 (05) :1495-1502
[6]   Expression of human herpesvirus 8 in primary pulmonary hypertension [J].
Cool, CD ;
Rai, PR ;
Yeager, ME ;
Hernandez-Saavedra, D ;
Serls, AE ;
Bull, TM ;
Geraci, MW ;
Brown, KK ;
Routes, JM ;
Tuder, RM ;
Voelkel, NF .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (12) :1113-1122
[7]   Overexpression of matrix metalloproteinase-7 in pulmonary fibrosis [J].
Cosgrove, GP ;
Schwarz, MI ;
Geraci, MW ;
Brown, KK ;
Worthen, GS .
CHEST, 2002, 121 (03) :25S-26S
[8]   Ongoing viral replication is required for gammaherpesvirus 68-induced vascular damage [J].
Dal Conto, AJ ;
Virgin, HW ;
Speck, SH .
JOURNAL OF VIROLOGY, 2000, 74 (23) :11304-11310
[9]   MULTIPLE DEFECTS OF IMMUNE CELL-FUNCTION IN MICE WITH DISRUPTED INTERFERON-GAMMA GENES [J].
DALTON, DK ;
PITTSMEEK, S ;
KESHAV, S ;
FIGARI, IS ;
BRADLEY, A ;
STEWART, TA .
SCIENCE, 1993, 259 (5102) :1739-1742
[10]   Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis [J].
Ebina, M ;
Shimizukawa, M ;
Shibata, N ;
Kimura, Y ;
Suzuki, T ;
Endo, M ;
Sasano, H ;
Kondo, T ;
Nukiwa, T .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2004, 169 (11) :1203-1208