The Expression of AQP1 IS Modified in Lung of Patients With Idiopathic Pulmonary Fibrosis: Addressing a Possible New Target

Abstract

Activation of the epithelial-mesenchymal transition process (EMT) by which alveolar cells in human lung tissue undergo differentiation giving rise to a mesenchymal phenotype (fibroblast/miofibroblasts) has been well recognized as a key element in the origin of idiopathic pulmonary fibrosis (IPF). Here we analyzed expression of AQP1 in lung biopsies of patients diagnosed with IPF, and compared it to biopsies derived from patients with diverse lung pneumonies, such as hypersensitivity pneumonitis, sarcoidosis or normal lungs. Immunostaining for AQP1 showed a clear increment of AQP1 localized in the alveolar epithelium in biopsies from IPF patients alone. Moreover, to examine the possible participation of AQP1 in the pathophysiology of IPF, we evaluated its role in the pro-fibrotic transformation induced by transforming growth factor (TGF-β) in vitro. Human alveolar epithelial cells (A549), and fibroblasts derived from an IPF patient (LL29), or fibroblasts from healthy normal lung tissue (MRC-5), were treated with TGF-β, and levels of expression of AQP1, as well as those of E-cadherin, vimentin, α-SMA and collagen were analyzed by RT-qPCR, western blot and immunohistochemistry. An increase of AQP1 mRNA and protein after TGF-β treatment (4–72h) was observed either in A549 or IPF fibroblast-LL29 but not in MRC-5 fibroblasts. A gradual reduction of E-cadherin, and increased expression of vimentin, with no changes in α-SMA levels were observed in A549. Whereas in LL29 and MRC-5, TGF-β1 elicited a large production of collagen and α-SMA that was significantly greater in IPF fibroblast-LL29. Changes observed are consistent with activation of EMT by TGF-β, but whether modifications in AQP1 expression are responsible or independent events occurring at the same time is still unknown. Our results suggest that AQP1 plays a role in the pro-fibrotic TGF-β action and contributes to the etiology and pathophysiology of IPF. Understanding AQP1's role will help us comprehend the fate of this disease.

Aquaporins in lung health and disease: Emerging roles, regulation, and clinical implications

“…[58]. Screening of human IPF lung biopsies revealed clearly elevated AQP1 levels in alveolar epithelia [59]. In vitro analysis in this study comparing IPF patient-derived versus healthy lung-derived fibroblasts showed AQP1 induction in response to TGF-β treatment in the former, implying AQP1 role in the pro-fibrotic TGF-β action and IPF etiology/pathophysiology.…”

Upregulation of Aquaporin 1 Mediates Increased Migration and Proliferation in Pulmonary Vascular Cells From the Rat SU5416/Hypoxia Model of Pulmonary Hypertension

“…It should be noted that the previous studies exploring the effect of deleting AQP1 on hypoxia-induced PH did not do so in a cell-type-specific manner, and various cells within the lung have been shown to express AQP1. For example, AQP1 expression has been reported in human and rat PASMCs (Leggett et al, 2012;Schuoler et al, 2017), macrophages (Rabolli et al, 2014;Tyteca et al, 2015), human activated T and B cells (Moon et al, 2004) and human and mouse type II pneumocytes (Effros et al, 1997;Galan-Cobo et al, 2018); however, staining for AQP1 was not observed in rat alveolar epithelium (Nielsen et al, 1997) or mouse type I cells (Effros et al, 1997). Thus, while the reduced development of hypoxiainduced PH in the previous studies could have resulted from the loss of AQP1 in PASMCs or MVECs, a role for AQP1 in other cell types cannot be ruled out at this point.…”

Glycyrrhizic Acid Attenuates Pulmonary Fibrosis of Silicosis by Inhibiting the Interaction between HMGB1 and BRG1 through PI3K/Akt/mTOR Pathway

“…However, the specific pathogenesis has not been completely clear. The study of mouse model [ 3 , 4 ] and patients with idiopathic pulmonary fibrosis (IPF) [ 5 ] showed that there was a close relationship between the epithelial–mesenchymal transition (EMT) and the process of pulmonary fibrosis. EMT is a biological process in which epithelial cells transform into cells with a mesenchymal phenotype, which is characterized by decreased expression of epithelial markers and increased expression of mesenchymal markers.…”