Role of Endoplasmic Reticulum Stress in Age-Related Susceptibility to Lung Fibrosis

Abstract

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 gherpesvirus infection, we infected young (2-3 mo) and old (>18 mo) C57BL/6 mice with the murine gherpesvirus 68. Acute murine gherpesvirus 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-b 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 Xbox-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.

Asbestos-induced Disruption of Calcium Homeostasis Induces Endoplasmic Reticulum Stress in Macrophages

“…We found that chrysotile exposure increased expression of various chaperone genes (endoplasmic-resident protein 72, GRP94, and protein kinase inhibitor 58-kDa) as well as other ER stress markers including ERO1-␣ and CHOP. Prior studies have evaluated the role of ER stress in inducing apoptosis in AEC as a potential mechanism in the pathogenesis of pulmonary fibrosis (8,9,11,12,34). Our findings clearly reveal ER stress in chrysotile-exposed macrophages; however, we found no significant apoptosis in alveolar macrophages from chrysotile-exposed mice.…”

“…6F). Because ER stress has been linked to increased apoptosis in AEC (8,9,11,12) in fibrotic lung, we determined if ER stress was associated with increased apoptosis in mouse BAL cells. There was no difference in apoptosis in alveolar macrophages from chrysotile-or TiO 2 -exposed mice, as measured by caspase-3 (Fig.…”

“…Regarding fibrosis, most available evidence indicates that ER stress enhances the vulnerability of structural cells such as AECs and fibroblasts to fibrotic stimuli. In these studies, ER stress and UPR in AECs has been associated with herpesvirus infection (9,11), altered surfactant protein processing (9), expression of mutant surfactant proteins (9,10,34,35), apoptosis (8,11,12), epithelial-mesenchymal transitions (7), and induction of an inflammatory response (35) that ultimately leads to a profibrotic environment in lung tissue (2,3). To our knowledge, no studies have examined the UPR in macrophages in the setting of lung fibrosis.…”

“…ER stress in AECs can be induced by mutations in surfactant protein C (8,9), mutations in SPA (10), and chronic herpesvirus infection (9,11), and ER stress can result in intrinsic apoptosis secondary to mitochondrial dysfunction (12). UPR markers and increased collagen Type I expression have been observed in fibroblasts of fibrotic lungs, a response likely mediated by activation of TGF-␤ signaling (7).…”

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

“…Senescence, mitochondrial dysfunction, and insufficient autophagy in the aging lung might have implications in maladaptive responses to stress. For instance, elderly mice are more vulnerable to fibrosis after injury or stress (17,21,22) and have a lower capacity for normal repair after damage (23). In this context, our group has shown that the lung's protective mechanisms against injury, such as mesenchymal stem cell differentiation, are also impaired with age (24).…”