scholarly journals The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes

2015 ◽  
Vol 308 (3) ◽  
pp. L229-L252 ◽  
Author(s):  
Steven C. Pugliese ◽  
Jens M. Poth ◽  
Mehdi A. Fini ◽  
Andrea Olschewski ◽  
Karim C. El Kasmi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Signaling Pathways ◽  
Vascular Remodeling ◽  
Mesenchymal Cells ◽  
World Health ◽  
Small Subset ◽  
Cellular Interactions ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Pulmonary Hypertension ◽  
Group I

Hypoxic pulmonary hypertension (PH) comprises a heterogeneous group of diseases sharing the common feature of chronic hypoxia-induced pulmonary vascular remodeling. The disease is usually characterized by mild to moderate pulmonary vascular remodeling that is largely thought to be reversible compared with the progressive irreversible disease seen in World Health Organization (WHO) group I disease. However, in these patients, the presence of PH significantly worsens morbidity and mortality. In addition, a small subset of patients with hypoxic PH develop “out-of-proportion” severe pulmonary hypertension characterized by pulmonary vascular remodeling that is irreversible and similar to that in WHO group I disease. In all cases of hypoxia-related vascular remodeling and PH, inflammation, particularly persistent inflammation, is thought to play a role. This review focuses on the effects of hypoxia on pulmonary vascular cells and the signaling pathways involved in the initiation and perpetuation of vascular inflammation, especially as they relate to vascular remodeling and transition to chronic irreversible PH. We hypothesize that the combination of hypoxia and local tissue factors/cytokines (“second hit”) antagonizes tissue homeostatic cellular interactions between mesenchymal cells (fibroblasts and/or smooth muscle cells) and macrophages and arrests these cells in an epigenetically locked and permanently activated proremodeling and proinflammatory phenotype. This aberrant cellular cross-talk between mesenchymal cells and macrophages promotes transition to chronic nonresolving inflammation and vascular remodeling, perpetuating PH. A better understanding of these signaling pathways may lead to the development of specific therapeutic targets, as none are currently available for WHO group III disease.

scholarly journals Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Mingzhou Guo ◽  
Mengzhe Zhang ◽  
Xiaopei Cao ◽  
Xiaoyu Fang ◽  
Ke Li ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Vascular Remodeling ◽  
Cell Surface Receptor ◽  
Cell Counting ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Pulmonary Hypertension ◽  
And Migration

Abstract Background Hypoxic pulmonary hypertension (HPH) is a chronic progressive advanced disorder pathologically characterized by pulmonary vascular remodeling. Notch4 as a cell surface receptor is critical for vascular development. However, little is known about the role and mechanism of Notch4 in the development of hypoxic vascular remodeling. Methods Lung tissue samples were collected to detect the expression of Notch4 from patients with HPH and matched controls. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured in hypoxic and normoxic conditions. Real-time quantitative PCR and western blotting were used to examine the mRNA and protein levels of Notch4. HPASMCs were transfected with small interference RNA (siRNA) against Notch4 or Notch4 overexpression plasmid, respectively. Cell viability, cell proliferation, apoptosis, and migration were assessed using Cell Counting Kit-8, Edu, Annexin-V/PI, and Transwell assay. The interaction between Notch4 and ERK, JNK, P38 MAPK were analyzed by co-immunoprecipitation. Adeno-associated virus 1-mediated siRNA against Notch4 (AAV1-si-Notch4) was injected into the airways of hypoxic rats. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Results In this study, we demonstrate that Notch4 is highly expressed in the media of pulmonary vascular and is upregulated in lung tissues from patients with HPH and HPH rats compared with control groups. In vitro, hypoxia induces the high expression of Delta-4 and Notch4 in HPASMCs. The increased expression of Notch4 promotes HPASMCs proliferation and migration and inhibits cells apoptosis via ERK, JNK, P38 signaling pathways. Furthermore, co-immunoprecipitation result elucidates the interaction between Notch4 and ERK/JNK/P38. In vivo, silencing Notch4 partly abolished the increase in RVSP and pulmonary vascular remodeling caused by hypoxia in HPH rats. Conclusions These findings reveal an important role of the Notch4-ERK/JNK/P38 MAPK axis in hypoxic pulmonary remodeling and provide a potential therapeutic target for patients with HPH.

scholarly journals The alveolar epithelial cells are involved in pulmonary vascular remodeling and constriction of hypoxic pulmonary hypertension

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yanxia Wang ◽  
Xiaoming Li ◽  
Wen Niu ◽  
Jian Chen ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Pulmonary Hypertension ◽  
Epithelial Cells ◽  
Pulmonary Artery ◽  
Vascular Remodeling ◽  
Culture Medium ◽  
Alveolar Epithelial Cells ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Pulmonary Hypertension ◽  
Alveolar Epithelial

Abstract Background Hypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. Alveolar epithelial cells (AECs) primarily sense alveolar hypoxia, but the role of AECs in HPH remains unclear. In this study, we explored whether AECs are involved in pulmonary vascular remodeling and constriction. Methods In the constructed rat HPH model, hemodynamic and morphological characteristics were measured. By treating AECs with hypoxia, we further detected the levels of superoxide dismutase 2 (SOD2), catalase (CAT), reactive oxygen species (ROS) and hydrogen peroxide (H2O2), respectively. To detect the effects of AECs on pulmonary vascular remodeling and constriction, AECs and pulmonary artery smooth cells (PASMCs) were co-cultured under hypoxia, and PASMCs and isolated pulmonary artery (PA) were treated with AECs hypoxic culture medium. In addition, to explore the mechanism of AECs on pulmonary vascular remodeling and constriction, ROS inhibitor N-acetylcysteine (NAC) was used. Results Hypoxia caused pulmonary vascular remodeling and increased pulmonary artery pressure, but had little effect on non-pulmonary vessels in vivo. Meanwhile, in vitro, hypoxia promoted the imbalance of SOD2 and CAT in AECs, leading to increased ROS and hydrogen peroxide (H2O2) production in the AECs culture medium. In addition, AECs caused the proliferation of co-cultured PASMCs under hypoxia, and the hypoxic culture medium of AECs enhanced the constriction of isolated PA. However, treatment with ROS inhibitor NAC effectively alleviated the above effects. Conclusion The findings of present study demonstrated that AECs were involved in pulmonary vascular remodeling and constriction under hypoxia by paracrine H2O2 into the pulmonary vascular microenvironment.

Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats

1995 ◽  
Vol 79 (6) ◽  
pp. 2122-2131 ◽  
Author(s):  
S. J. Chen ◽  
Y. F. Chen ◽  
Q. C. Meng ◽  
J. Durand ◽  
V. S. Dicarlo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Acute Hypoxia ◽  
Subsequent Development ◽  
Hypoxic Exposure ◽  
Heart Hypertrophy ◽  
Endothelin Receptor ◽  
Right Heart ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Pulmonary Hypertension

The current study examined the effects of bosentan, an orally active antagonist of endothelin-A and -B receptors, on the development and maintenance of hypoxia (10% O2)-induced pulmonary hypertension and vascular remodeling in the rat. Pretreatment with bosentan (100 mg.kg-1.day-1, 1 gavage/day for 2 days) completely blocked the pulmonary vasoconstrictor response to acute hypoxia. Chronic bosentan treatment (100 mg.kg-1.day-1 po in the food) instituted 48 h before hypoxic exposure prevented the subsequent development of pulmonary hypertension, attenuated the associated right heart hypertrophy, and prevented the remodeling of small (50–100 microns) pulmonary arteries without altering systemic arterial pressure. Institution of bosentan treatment (for 4 wk) after 2 wk of hypoxia produced a significant reversal of established hypoxia-induced pulmonary hypertension (from 36 +/- 1 to 25 +/- 1 mmHg), right heart hypertrophy, and pulmonary vascular remodeling despite continuing hypoxic exposure. These findings support the hypothesis that endogenous endothelin-1 plays a major role in hypoxic pulmonary vasoconstriction and/or hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that endothelin-receptor blockade may be useful in the treatment of hypoxic pulmonary hypertension humans.

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