Functional Roles for CD26/DPP4 in Mediating Inflammatory Responses of Pulmonary Vascular Endothelial Cells.

Yukiko Takahashi,Yoshinori Hasegawa,Koichiro Tatsumi,Takuji Suzuki,Takeshi Kawasaki,Hironori Sato,Osamu Ohara,Steven M. Dudek

doi:10.3390/cells10123508

Abstract

Excessive inflammation in the lung is a primary cause of acute respiratory distress syndrome (ARDS). CD26/dipeptidyl peptidase-4 (DPP4) is a transmembrane protein that is expressed in various cell types and exerts multiple pleiotropic effects. We recently reported that pharmacological CD26/DPP4 inhibition ameliorated lipopolysaccharide (LPS)-induced lung injury in mice and exerted anti-inflammatory effects on human lung microvascular endothelial cells (HLMVECs), in vitro. However, the mechanistic roles of CD26/DPP4 in lung injury and its effects on HLMVECs remain unclear. In this study, transcriptome analysis, followed by various confirmation experiments using siRNA in cultured HLMVECs, are performed to evaluate the role of CD26/DPP4 in response to the pro-inflammatory involved in inflammation, barrier function, and regenerative processes in HLMVECs after pro-inflammatory stimulation. These are all functions that are closely related to the pathophysiology and repair process of lung injury. Confirmatory experiments using flow cytometry; enzyme-linked immunosorbent assay; quantitative polymerase chain reaction; dextran permeability assay; WST-8 assay; wound healing assay; and tube formation assay, reveal that the reduction of CD26/DPP4 via siRNA is associated with altered parameters of inflammation, barrier function, and the regenerative processes in HLMVECs. Thus, CD26/DPP4 can play a pathological role in mediating injury in pulmonary endothelial cells. CD26/DPP4 inhibition can be a new therapeutic strategy for inflammatory lung diseases, involving pulmonary vascular damage.

Highlights

Acute respiratory distress syndrome (ARDS) is characterized by enhanced pulmonary vascular permeability leading to a non-cardiac pulmonary edema
The increased expression of the adhesion molecules is an important step in the inflammatory response and is one of the hallmarks of lung injury; we evaluated whether the reduction of CD26/dipeptidyl peptidase-4 (DPP4) levels using siRNA for DPP4 (siRNA) affects the expression of ICAM-1 in human lung microvascular endothelial cells (HLMVECs)
0.045165 ecules is an important step in the inflammatory response and is one of the hallmarks of lung injury; we evaluated whether the reduction of CD26/DPP4 levels using siRNA affects the expression of ICAM-1 in HLMVECs

Summary

Introduction

Acute respiratory distress syndrome (ARDS) is characterized by enhanced pulmonary vascular permeability leading to a non-cardiac pulmonary edema. Excessive inflammation in the lungs is a major trigger for ARDS. The pathophysiology of ARDS includes inflammation; the uncontrolled activation of leukocytes, platelets, and coagulation systems; and increased permeability of the endothelial and alveolar epithelial barriers [1]. Pulmonary vascular endothelial cells and lung epithelial cells generate pro-inflammatory signals during ARDS progression [2]. The pathological phases of ARDS are classified into three stages: exudative, proliferative, and fibrotic. The exudative stage is characterized by increased pulmonary vascular permeability and increased neutrophils in the alveolar septum and airspaces, along with the death of epithelial and endothelial cells. The proliferative stage is characterized by fibroblast proliferation and type 2 pneumocyte hyperplasia [3]

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