Figure 3.

Overview of some of the key pathogenetic mechanisms in UIP/IPF. Following an unidentified insult, alveolar epithelial cells become injured and delayed re-epithelialization leads to a denuded, disrupted basement membrane. A fibrin clot forms early and serves as a provisional matrix for the migration and proliferation of reparative type I alveolar epithelial cells. Angiogenic factors may be elaborated, leading to the formation of nascent vasculature early in the disease process. Neutrophils secrete pro-inflammatory mediators, reactive oxygen species (ROS) and MMPs, while recruited lymphocytes elaborate the Th2-type cytokines, IL-4 and IL-13. Fibroblasts migrate into the wound and produce extracellular matrix (ECM) proteins and mediators such as angiotensin II which may further promote alveolar epithelial cell apoptosis. Alveolar macrophages and epithelial cells secrete TGF-β1, which promotes myofibroblast differentiation, increases ECM production, and inhibits apoptosis of fibroblasts/myofibroblasts. As ECM deposition progresses, regression of blood vessels may occur. Reciprocal communication between alveolar epithelial cells and mesenchymal cells results in a ‘positive feedback loop’ that promotes ongoing fibrosis and destruction of alveolar architecture