Beyond inflammation: alarmins as critical drivers of pulmonary fibrosis

: Pulmonary fibrosis is a chronic respiratory disorder characterised by an overproduction and aberrant deposition of fibrotic tissue in the lungs. This narrative review focuses on the pivotal role played by epithelial alarmins, primarily thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33, in the pathogenesis of idiopathic pulmonary fibrosis and connective tissue disease-associated interstitial lung disease. It considers their function as damage-associated molecular patterns and the attraction of both innate and adaptive immune cells that these patterns elicit, thereby playing a significant role in the immune response to fibrosis. Epithelial alarmins play a dynamic role in regulating fibroblast-macrophage interactions during lung injury and this process influences macrophage polarisation and drives the epithelial-mesenchymal transition. It is evident that these epithelial alarmins play a key role in activating the type 2 immune network and, given the established importance of type 2 inflammatory responses in pulmonary fibrosis, there is significant interest in the study of epithelial alarmins and their contribution to profibrotic type 2 immune responses. A deeper understanding of this area could result in the conceptualisation of new targeted therapies.