Alveolar epithelial-to-mesenchymal transition in scleroderma interstitial lung disease: Technical challenges, available evidence and therapeutic perspectives

Abstract

The alveolar epithelial-to-mesenchymal transition is the process of transformation of differentiated epithelial cells into mesenchymal-like cells through functional and morphological changes. A partial epithelial-to-mesenchymal transition process can indirectly contribute to lung fibrosis through a paracrine stimulation of the surrounding cells, while a finalized process could also directly enhance the pool of pulmonary fibroblasts and the extracellular matrix deposition. The direct demonstration of alveolar epithelial-to-mesenchymal transition in scleroderma-related interstitial lung disease is challenging due to technical pitfalls and the limited availability of lung tissue samples. Similarly, any inference on epithelial-to-mesenchymal transition occurrence driven from preclinical models should consider the limitations of cell cultures and animal models. Notwithstanding, while the occurrence or the relevance of this phenomenon in scleroderma-related interstitial lung disease have not been directly and conclusively demonstrated until now, pre-clinical and clinical evidence supports the potential role of epithelial-to-mesenchymal transition in the development and progression of lung fibrosis. Evidence consolidation on scleroderma-related interstitial lung disease epithelial-to-mesenchymal transition would pave the way for new therapeutic opportunities to prevent, slow or even reverse lung fibrosis, drawing lessons from current research lines in neoplastic epithelial-to-mesenchymal transition.

Low Carbon Monoxide Diffusing Capacity, Patient-Reported Measures and Reduced Nailfold Capillary Density Are Associated with Interstitial Lung Disease in Systemic Sclerosis

“…Some studies suggested that gastro-oesophageal reflux may play a significant role in the pathogenesis of SSc-ILD [38][39][40]. Abnormalities in oesophageal peristalsis and the reduced oesophageal sphincter pressure are believed to lead to recurring micro-aspiration of gastric acid into the respiratory tract, resulting in chronic inflammation and progressive tissue damage [39][40][41]. Results of our study provide evidence that the self-administration of Gerd-Q, a validated questionnaire addressing the symptoms of gastro-oesophageal reflux [24,25,42], can be used to assess the presence of SSc-ILD, being this association more likely when the score is >7.…”

Low-Carbon Monoxide Diffusing Capacity, Patient-Reported Measures and Reduced Nailfold Capillary Density Are Associated with Interstitial Lung Disease in Systemic Sclerosis

“…Some studies suggested that gastro-oesophageal reflux may play a significant role in the pathogenesis of SSc-ILD [ 38 , 39 , 40 ]. Abnormalities in oesophageal peristalsis and the reduced oesophageal sphincter pressure are believed to lead to recurring micro-aspiration of gastric acid into the respiratory tract, resulting in chronic inflammation and progressive tissue damage [ 39 , 40 , 41 ]. Results of our study provide evidence that the self-administration of Gerd-Q, a validated questionnaire addressing the symptoms of gastro-oesophageal reflux [ 24 , 25 , 42 ], can be used to assess the presence of SSc-ILD, as this association is more likely when the score is >7.…”

“…Microvascular damage is one of the characteristic findings in SSc, which may occur early in the disease course. Moreover, it is thought to be strongly involved in the SSc-ILD pathogenesis [ 2 , 14 , 41 , 43 ]. A causal relationship between microcirculation abnormalities and pulmonary fibrosis could be found in the association of SSc-ILD with structural capillary changes detected by NVC [ 13 , 14 ].…”

“…It seems clear that the four measurements represent the clinical/biometric interface of the pathogenesis of pulmonary involvement, especially of the early phase of SSc (alteration of alveolar gas exchanges, chronic inflammation due to gastric micro-aspirations, chief role of autoimmune-type microcirculation damage as a primer of mesenchymal cell activation) [ 3 , 11 , 41 , 43 ] and appear suitable to be used as variables indicating SSc-ILD [ 11 ].…”