Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial–mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci (FF) represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: (1) from resident fibroblasts, (2) from bone marrow-derived progenitors of fibroblasts, and (3) from alveolar epithelial cells that have undergone epithelial-mesenchymal transition (EMT). We found that FF dissociated capillary vessels from the alveolar epithelia, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100 μm below the alveolar epithelia. Furthermore, the alveolar epithelial cells covering the FF exhibited a partial EMT phenotype. In addition, normal human alveolar epithelial cells in vitro underwent dynamic EMT in response to transforming growth factor-β signaling within 72 h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the alveolar epithelia and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned alveolar epithelia located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the alveolar septa, thus destroying them. Consequently, collapse of the alveolar septa is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-β signaling, which can suppress EMT of the alveolar epithelial cells in vitro, is a potential strategy for treating IPF.

Epithelial‐to‐mesenchymal transition and its role in EGFR‐mutant lung adenocarcinoma and idiopathic pulmonary fibrosis

“…However, we have uncovered that FF are localized between them, and push the preexisting capillaries and elastic fibers down approximately 100 µm below the epithelia (Fig. ) reveals that although FF are covered with alveolar epithelia that are uniformly and mostly positive for CK7 and TTF‐1, respectively, some alveolar epithelia over FF are flat rather than round, express vimentin, and lose TTF‐1 expression .…”

“…) reveals that although FF are covered with alveolar epithelia that are uniformly and mostly positive for CK7 and TTF‐1, respectively, some alveolar epithelia over FF are flat rather than round, express vimentin, and lose TTF‐1 expression . This suggests that some alveolar epithelia covering FF appear to have acquired a partial EMT phenotype.…”

“…FF are present in the background of collagen deposition, reflect the temporal heterogeneity of the process, and indicate that fibrosis in the IPF lung is currently ongoing . We recently conducted a series of experiments to test the hypothesis that fibroblasts in FFs are derived from mesenchymal alveolar epithelial cells . It is well‐known that epithelial and capillary basement membranes in the alveolar septa are irregularly fused in physiological conditions, and Figure b shows that CD34‐expressing capillary vessels are located immediately under the CK7‐positive alveolar epithelia in the almost normal lung tissue.…”

“…Although the histopathological findings of IPF lung tissues suggest that non‐neoplastic alveolar epithelial cells can contribute to FF formation through EMT, little was reported on whether and to what extent normal peripheral lung epithelial cells, but not lung adenocarcinoma cells, can undergo EMT. However, we were recently able to analyze normal peripheral lung epithelial cells, termed Human Lung (HuL) cells, in vitro and demonstrate the phenotypic plasticity of these cells . The HuL cells obtained from several individuals express TTF‐1 at mRNA and protein levels, and undergo dynamic EMT or mesenchymal‐to‐epithelial transition (MET) in the presence or absence, respectively, of TGF‐β signaling within 72 h (Fig.…”

Posttranscriptional control of airway inflammation

“…Peptidyl‐prolyl cis / trans isomerase (Pin1) was shown to induce HuR to bind and stabilize TGF‐β mRNA resulting in enhanced collagen expression and peribronchiolar fibrosis in mice . Studies have indicated that EMT occurring within the alveolar epithelium plays a key role in fibrotic lung remodeling in this disease . Surfactant protein C (SFTPC) is a key component of lung surfactant, which maintains alveolar epithelial function and integrity .…”