Apelin-13 Ameliorates LPS-Induced Endothelial-to-Mesenchymal Transition and Post–acute Lung Injury Pulmonary Fibrosis by Suppressing Transforming Growth Factor-Β1 Signaling

Abstract

The pathophysiology of acute respiratory distress syndrome (ARDS) involves cytokine storms, alveolar-capillary barrier destruction, and fibrotic progression. Pulmonary interstitial fibrosis is an important factor affecting the prognosis of ARDS patients. Endothelial-to-mesenchymal transition (EndMT) plays an important role in the development of fibrotic diseases, and the occurrence of EndMT has been observed in experimental models of LPS-induced acute lung injury (ALI). Apelin is an endogenous active polypeptide that plays an important role in maintaining endothelial cell homeostasis and inhibiting fibrotic progression in various diseases. However, whether apelin attenuates EndMT in ALI and post-ALI pulmonary fibrosis remains unclear. We analyzed the serum levels of apelin-13 in patients with sepsis-associated ARDS to examine its possible clinical value. A murine model of LPS-induced pulmonary fibrosis and an LPS-challenged endothelial cell injury model were used to analyze the protective effect and underlying mechanism of apelin-13. Mice were treated with apelin-13 by i.p. injection, and human pulmonary microvascular endothelial cells were incubated with apelin-13 in vitro. We found that the circulating apelin-13 levels were significantly elevated in sepsis-associated ARDS patients compared with healthy controls. Our study also confirmed that LPS induced EndMT progression and pulmonary fibrosis, which were characterized by decreased CD31 expression and increased α-smooth muscle actin expression and collagen deposition. LPS also stimulated the production of transforming growth factor β1 and activated the Smad signaling pathway. However, apelin-13 treatment significantly attenuated these changes. Our findings suggest that apelin-13 may be a novel biomarker in patients with sepsis-associated ARDS. These results demonstrate that apelin-13 ameliorates LPS-induced EndMT and post-ALI pulmonary fibrosis by suppressing transforming growth factor β1 signaling.

Chronic Effects of Apelin on Cardiovascular Regulation and Angiotensin II-Induced Hypertension

“…The results from this study indicate that the chronic administration of apelin does not significantly improve Ang II-induced elevation in blood pressure and cardiac remodeling, indicating that apelin does not interact with AT1 receptors, although APJ receptors share high sequence similarity with AT1 receptors [6]. However, this result is not consistent with previous studies showing that the chronic administration of apelin is effective in treating preeclampsia, pulmonary arterial hypertension, and myocardial infarction-associated cardiac remodeling [21][22][23]. One possible explanation of this controversy could be due to the hypoxic conditions in those disorders.…”

The Apelin/APJ System: A Potential Therapeutic Target for Sepsis

“…Furthermore, patients with mild ARDS had lower Apelin levels than patients with severe ARDS, and survivors had higher Apelin levels than non-survivors ( Figure 3B ). Liu et al 45 also confirmed significantly higher serum Apelin levels in 28 patients with sepsis-related ARDS compared with 20 healthy volunteers and a higher level in survivors compared with non-survivors.…”

Α2-Adrenoreceptor ANTAGONIST AMELIORATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY SUPPRESSING NOREPINEPHRINE-MEDIATED FIBROBLAST DIFFERENTIATION VIA INHIBITING PKC ACTIVATION

“…Tissue fibrosis is typically characterized by excessive proliferation of myofibroblasts, abnormal increases, and excessive deposition of extracellular matrix (28). Pulmonary fibroblasts are the key cells that synthesize and secrete collagen into the extracellular matrix of mesenchymal tissues, and their abnormal behavior results in pulmonary fibrosis (29).…”