Pathobiology of pulmonary fibrosis

Pulmonary fibrosis is characterized by an increase in lung matrix and alterations in the numbers and spatial relationships of lung parenchymal cells. The increase in matrix results from a proliferation and "activation" of fibroblasts (FB) with increased production and deposition of matrix macromolecules at sites of lung injury. Connective tissue cell activation is associated with increased gene expression of collagens, fibronectin, proteoglycans and other matrix components; cytoskeletal alterations; and probably also with changes in the expression of matrix receptors and matrix-degrading enzymes and inhibitors. The fibroproliferative reaction involves the participation of a variety of cytokines and inflammatory mediators by resident and inflammatory cells at sites of lung injury. Thickening of the alveolar wall can result secondary to matrix deposition within the interstitium and as a result of "mural incorporation" of organized airspace exudate. However, marked structural remodeling of the gas-exchange tissues, with the development of honeycomb lung, involves airspace fibrosis and alveolar collapse. The latter processes lead to areas of airspace obliteration secondary to airspace filling, and to fibrous adhesion of collapsed septa. The extent of airspace obliteration is determined largely by the severity or extent of epithelial injury. Although lung fibrosis is usually irreversible, the activated state is reversible after clearance of exudate and reepithelialization. A continuing and seemingly autonomous fibroproliferative reaction can result in the face of ongoing injury and delayed repair.