The mitogen-activated protein kinase kinase kinase (MAP3K) ASK1 has been described as a key enzyme in the transduction of reactive oxygene species (ROS) signaling, that mediates through activation of effector mitogen activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinases (JNK1/2) diverse cellular responses involving cell proliferation, differentiation and apoptosis. ASK1 is also activated under severe endoplasmic reticulum stress through the formation of a proapoptotic signalosome consisting of phosphorylated inositol-requiring protein 1 (p-IRE1?), TNF receptor-associated factor-2 (TRAF2) and ASK1. We found increased activation of IRE1?, ASK1, p38 and JNK1/2 in alveolar type-II cells (AECII) as well as fibroblast foci of idiopathic pulmonary fibrosis (IPF)-lungs, presuming a proapoptotic function in IPF-AECII, but a survival-related role in supporting proliferation and expansion of IPF-fibroblasts. We thus suggested that loss of Ask1 might protect mice from epithelial apoptosis and consecutive lung fibrosis in the bleomycin-mouse model. Surprisingly, Ask1^(-/-) mice revealed much more and aggravated development of lung fibrosis than wildtype mice in response to bleomycin. Moreover, apoptotic signalling was significantly upregulated in Ask1^(-/-) vs. wildtype mice at day 7 post bleomycin. These results indicate that Ask1 may have pivotal cellular functions which may not be deleted under conditions of lung fibrosis. Therefore, we wish to evaluate the therapeutic effects of blockade of Ask1-kinase activation in bleomycin-injured wildtype mice by using the Ask1 inhibitor selonsertib, as this drug attenuated profibrotic signalling in cultured precision-cut lung slices from IPF-lungs.