Increased susceptibility to gammaherpesvirus-induced lung fibrosis of transgenic mice with conditional overexpression of the ER-stress-factor Chop in alveolar epithelium

The main characteristic of idiopathic pulmonary fibrosis (IPF) is ER-stress and apoptosis in alveolar type-II cells (AECII), which in consequence cause chronic epithelial injury and progressive lung fibrosis. We developed double-transgenic mice expressing the proapoptotic ER-stress-factor Chop exclusively in AECII by using the “Tetracycline-On-system” (SP-C rtTA/tetO7-Chop). In response to 28 days doxycycline-feeding (Dox+), nuclear Chop-overexpression in AECII resulted in AECII-apoptosis, but not in development of lung fibrosis. We then infected Chop transgenic mice after 28 days transgene-induction (Dox+), as well as without transgene induction (Dox-), intranasally with murine gammaherpesvirus-68 (MHV68). At 15 days post infection, mice were sacrificed and analyzed. Lungs of MHV68-infected (Dox+)-Chop-mice, but not of infected (Dox-)-Chop-mice or uninfected (Dox+)- and (Dox-)-Chop-mice, evidently showed thickening of alveolar septae and fibrotic remodeling. In addition, ER-stress- and strong apoptosis-induction (caspase-3/-9-activation, PARP1-cleavage) was observed in lungs of both MHV68-infected (Dox+)- and (Dox-)-Chop-mice versus controls, presumably due to virus-induced lung injury, but was more pronounced in the infected (Dox+)-Chop-mice. Further, MHV68-infected (Dox+)- as well as (Dox-)-Chop-mice indicated upregulation of profibrotic protein-expression versus controls, but was “biggest” in the infected (Dox+)-Chop-mice. We conclude that our transgenic Chop-mouse-model resembles human IPF, since IPF-patients have been defined as (genetically) susceptible individuals prone to develop disease with second hits.