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 (TSLP), IL-25, and IL-33 –, in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and connective tissue disease associated interstitial lung disease (CTD-ILD). 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.