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Published on: June 2, 2022
CMTM3 regulates vascular endothelial cell dysfunction by influencing pulmonary vascular endothelial permeability and
Ziyan Xiao1,2,3, Gang Zhou1,2, Haiyan Xue1,2,3
1Department of Critical Care Medicine, Peking University People's Hospital, Beijing, China.
Introduction:
CMTM3 is a member of the human chemokine-like factor superfamily. The mechanistic role of CMTM3 in acute respiratory distress syndrome (ARDS) is not known. This study investigated the role of CMTM3 in the progression of ARDS and its impact on the function of vascular endothelial cells.
Methods:
ARDS modeling in human umbilical vascular endothelial cells (HUVECs) was performed by treating with lipopolysaccharide (LPS) or hypoxia/reoxygenation. We assessed CMTM3 expression levels in the LPS- and hypoxia/reoxygenation-stimulated HUVEC cells. Furthermore, we assessed the role of CMTM3 in the permeability function and inflammatory response of the vascular endothelial cells under ARDS conditions using HUVEC cells with CMTM3 overexpression(adCMTM3) or knockdown(shCMTM3). Concurrently, we generated CMTM3 knockout (CMTM3ko) mice and evaluated the differences in pulmonary vascular permeability, inflammatory lung injury, and survival rates between the CMTM3ko-ARDS and WT-ARDS model mice.
Results:
HUVECs stimulated with LPS and hypoxia/reoxygenation showed significantly higher CMTM3 expression compared to the control group (p<0.05). Compared with the adsham-HUVECs, adCMTM3-HUVECs stimulated with LPS and hypoxia/reoxygenation demonstrated significantly higher cellular permeability (p<0.05) as well as IL-6 and TNF-α expression levels (p<0.05). Conversely, shCMTM3-HUVECs stimulated with LPS and hypoxia/reoxygenation showed significantly reduced cellular permeability as well as IL-6 and TNF-α expression levels (p<0.05). In vivo ARDS modeling experiments demonstrated that CMTM3-knockout ARDS mice exhibited significantly higher survival rates (p=0.0194) as well as significantly reduced lung injury and pulmonary vascular permeability (p<0.05) compared to the wild-type ARDS mice.
Discussion:
These findings demonstrated that CMTM3 played a critical role in the development of ARDS by influencing permeability of the pulmonary vascular endothelial cells and lung inflammation. Therefore, CMTM3 is a potential therapeutic target in ARDS.
Insights
Chemokine-like factor superfamily member CMTM3 significantly impacts acute respiratory distress syndrome (ARDS) by increasing vascular endothelial cell permeability and lung inflammation. CMTM3 knockout mice show improved survival and reduced lung injury, highlighting CMTM3 as a potential therapeutic target for ARDS.
Area of Science:
- Cell Biology
- Immunology
- Pulmonary Medicine
Background:
- Acute Respiratory Distress Syndrome (ARDS) is a critical condition with high mortality.
- The molecular mechanisms underlying ARDS progression, particularly involving vascular endothelial cells, require further elucidation.
- CMTM3, a member of the chemokine-like factor superfamily, has an unknown role in ARDS pathogenesis.
Purpose of the Study:
- To investigate the role of CMTM3 in the development and progression of ARDS.
- To determine the impact of CMTM3 on vascular endothelial cell function under ARDS conditions.
- To evaluate CMTM3 as a potential therapeutic target for ARDS.
Main Methods:
- ARDS models were established in human umbilical vascular endothelial cells (HUVECs) using lipopolysaccharide (LPS) or hypoxia/reoxygenation.
- CMTM3 expression was assessed in stimulated HUVECs.
- HUVECs with CMTM3 overexpression (adCMTM3) or knockdown (shCMTM3) were used to study cellular permeability and inflammatory marker (IL-6, TNF-α) expression.
- CMTM3 knockout (CMTM3ko) mice were generated to assess pulmonary vascular permeability, lung injury, and survival rates in an in vivo ARDS model.
Main Results:
- CMTM3 expression was significantly upregulated in LPS- and hypoxia/reoxygenation-stimulated HUVECs.
- Overexpression of CMTM3 in HUVECs exacerbated cellular permeability and IL-6/TNF-α expression under ARDS conditions.
- Knockdown of CMTM3 in HUVECs attenuated cellular permeability and inflammatory responses.
- CMTM3 knockout ARDS mice exhibited significantly higher survival rates and reduced lung injury and pulmonary vascular permeability compared to wild-type ARDS mice.
Conclusions:
- CMTM3 plays a critical role in ARDS development by modulating pulmonary vascular endothelial cell permeability and lung inflammation.
- Targeting CMTM3 presents a promising therapeutic strategy for mitigating ARDS severity and improving patient outcomes.
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