Role of endoplasmic reticulum stress in age-related susceptibility to lung fibrosis.
The incidence of idiopathic pulmonary fibrosis (IPF) increases with age. The mechanisms that underlie the age-dependent risk for IPF are unknown. Based on studies that suggest an association of IPF and γherpesvirus infection, we infected young (2-3 mo) and old (≥18 mo) C57BL/6 mice with the murine γherpesvirus 68. Acute murine γherpesvirus 68 infection in aging mice resulted in severe pneumonitis and fibrosis compared with young animals. Progressive clinical deterioration and lung fibrosis in the late chronic phase of infection was observed exclusively in old mice with diminution of tidal volume. Infected aging mice showed higher expression of transforming growth factor-β during the acute phase of infection. In addition, aging, infected mice showed elevation of proinflammatory cytokines and the fibrocyte recruitment chemokine, CXCL12, in bronchoalveolar lavage. Analyses of lytic virus infection and virus reactivation indicate that old mice were able to control chronic infection and elicit antivirus immune responses. However, old, infected mice showed a significant increase in apoptotic responses determined by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling assay, levels of caspase-3, and expression of the proapoptotitc molecule, Bcl-2 interacting mediator. Apoptosis of type II lung epithelial cells in aging lungs was accompanied by up-regulation of endoplasmic reticulum stress marker, binding immunoglobulin protein, and splicing of X-box-binding protein 1. These results indicate that the aging lung is more susceptible to injury and fibrosis associated with endoplasmic reticulum stress, apoptosis of type II lung epithelial cells, and activation of profibrotic pathways.
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Emory University, Atlanta, Georgia, USA.
Edilson
E
Torres-González
Marta
M
Bueno
Atsuko
A
Tanaka
Laurie T
LT
Krug
Dong-Sheng
DS
Cheng
Vasiliy V
VV
Polosukhin
Dan
D
Sorescu
William E
WE
Lawson
Timothy S
TS
Blackwell
Mauricio
M
Rojas
Ana L
AL
Mora
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013312:Stress, Physiological; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016212:Transforming Growth Factor beta