The pathogenesis of idiopathic pulmonary fibrosis: from "folies à deux" to "Culprit cell Trio"

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with poor survival affecting aging people. Although the etiology of IPF is “ufficially” considered as unknown, the pathogenesis of the disease has been substantially deciphered, revealing a complex scenario where different cellular and molecular mechanisms are involved. From the early seminal proposal of Selman et al. a consistent amount of data have confirmed the occurrence of a deranged crosstalk of epithelial and mesenchymal cells, and this paradigm replaced the previous mainstream “inflammatory” theory. The role of intrinsic defects affecting type-II pneumocytes/alveolar epithelial cells (AECII) became more precisely defined when genetic studies on familial pulmonary fibrosis (and also sporadic cases) revealed specific gene mutations interfering with the control of either telomere length or genes specifically expressed by AECII (surfactant proteins, ABCA). Taken together these observations suggest that the initial (etiologic) mechanism is caused by a senescence-related progressive loss of stem/precursor reparative functions of AECII. In this pathogenic scheme, the concurrent contribution of a variety of risk and noxious factors (genetic defects/predisposition, “natural” replicative senescence, and toxic substances such as cigarette smoke and pollution) may determine cell senescence and stem-cell exhaustion in predisposed areas of lung parenchyma (where high levels of mechanical stress occur).