The inflammation influence on pathological remodeling of pulmonary arteries in monocrotaline-induced pulmonary hypertension in rats

Abstract Aim To investigate the inflammation role on pathological remodeling of pulmonary arteries (PA) in monocrotaline-induced pulmonary hypertension (mPAH) in rats with joint assessment serum and tissue inflammatory biomarkers and the morphological arteries changes. Methods The mPAH was induced by a subcutaneous monocrotaline injection (60 mg/kg) in male rats and control group received a single saline solution. Baseline and every 2, 4, 6, 8 weeks after the serum concentrations of interleukin-6 (IL-6), interleukin-10 (IL-10) were measured by enzyme-linked immunosorbent assay; matrix metalloproteinase-9 (MMP-9), interleukin-1β (IL-1β), collagen type 1 and 3, smooth muscle actin α (SMA-α) in lung tissue were investigated immunohistochemically and quantitative measurements of intima and media thickness were done by planimetry. The functional activity neutrophil changes measured by chemiluminescence and fluorescent methods. Results The IL-10 increased after 2 weeks of mPAH (5,9 vs 0,6 pg/ml, p<0,05) vs control and then it decreased to initial values by 8 weeks (0,06 vs 0,62 pg/ml, p>0,05). The increasing IL-6 (30,3 vs 0,01 pg/ml, p<0,05) and the maximum expression of IL-1β in the lung tissue (0,119 vs 0,099 index of expression (IE), p<0,05) we observed 4 weeks after mPAH. The SMA-α (29,4 vs 40,2 IE, p<0,05) and MMP-9 (1,6 vs 0,8 IE, p<0,05) expression level significantly raised 4 weeks later vs control and remained in a high level until 8 week. A significant increase of type 1 collagen expression was observed at all phases of the experiment, and high level type 3 collagen expression was observed from 4 to 8 weeks (7,0 vs 10,4 IE, p<0,05). The histological characteristics of remodeling these were a thickening of the media (30,6 vs 56,0 μm, p<0,05) and the subintimal layer (1,6 vs 10,9 μm, p<0,05) of the PA. 2 weeks after mPAH cell priming occurred which manifested by modification ROS generation systems, decrease NADPH oxidase activity, increase of myeloperoxidase secretion (MPO), enhance of unbound cytosolic calcium ions, mitochondrial potential reduction. From 4 to 8 weeks an increase NADPH oxidase activity and MPO secretion was revealed into the extracellular environment which leads to overproduction of hypochlorous acid. This functional activity reprogramming of circulating neutrophils indicate associated with time-development of mPAH. Conclusion The inflammation is the most important mediator of pathological remodeling processes in mPA. The monocrotaline launches a neutrophil reaction at an early stage of PAH with changes their functional activity which leads to immune cells recruitment into the lung tissue, producing inflammation and proliferation biomarkers. The hyperplasia of smooth muscle cells and reconstruction of the extracellular matrix are the result of this process and leads to increase intima and media thickness. The high MMP-9, SMA-α, IL-6 activity in 6–8 weeks reflects maintenance local inflammatory potential. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Basic and applied sciences - medicine, subprogram “Diagnostics and therapy of diseases” on the assignment “To establish the molecular-cellular mechanisms of the development of irreversible remodeling of pulmonary vessels in pulmonary arterial hypertension in an experiment in vivo.”

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The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

International Journal of Molecular Sciences ◽

10.3390/ijms22094980 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4980

Author(s):

Inés Roger ◽

Javier Milara ◽

Paula Montero ◽

Julio Cortijo

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Vascular Remodeling ◽

Pulmonary Arteries ◽

Clinical Manifestations ◽

Different Types ◽

Artery Remodeling ◽

Stat Pathway ◽

Pulmonary Artery Remodeling

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

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Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00378.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. L1-L8 ◽

Cited By ~ 202

Author(s):

Enrique Arciniegas ◽

Maria G. Frid ◽

Ivor S. Douglas ◽

Kurt R. Stenmark

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Remodeling ◽

Serine Proteases ◽

Structural Changes ◽

Transforming Growth Factor ◽

Pulmonary Arteries ◽

Potential Contribution ◽

Mesenchymal Transition ◽

Endothelial Mesenchymal Transition

All forms of pulmonary hypertension are characterized by structural changes in pulmonary arteries. Increased numbers of cells expressing α-smooth muscle (α-SM) actin is a nearly universal finding in the remodeled artery. Traditionally, it was assumed that resident smooth muscle cells were the exclusive source of these newly appearing α-SM actin-expressing cells. However, rapidly emerging experimental evidence suggests other, alternative cellular sources of these cells. One possibility is that endothelial cells can transition into mesenchymal cells expressing α-SM actin and that this process contributes to the accumulation of SM-like cells in vascular pathologies. We review the evidence that endothelial-mesenchymal transition is an important contributor to cardiac and vascular development as well as to pathophysiological vascular remodeling. Recent work has provided evidence for the role of transforming growth factor-β, Wnt, and Notch signaling in this process. The potential roles of matrix metalloproteinases and serine proteases are also discussed. Importantly, endothelial-mesenchymal transition may be reversible. Thus insights into the mechanisms controlling endothelial-mesenchymal transition are relevant to vascular remodeling and are important as we consider new therapies aimed at reversing pulmonary vascular remodeling.

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Upregulation of ET-1 and its receptors and remodeling in small pulmonary veins under hypoxic conditions

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.6.l1104 ◽

2001 ◽

Vol 280 (6) ◽

pp. L1104-L1114 ◽

Cited By ~ 30

Author(s):

Hideki Takahashi ◽

Sanae Soma ◽

Masashi Muramatsu ◽

Masahiko Oka ◽

Yoshinosuke Fukuchi

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Remodeling ◽

Smooth Muscle Actin ◽

Pulmonary Veins ◽

Pulmonary Arteries ◽

Immunohistochemical Method ◽

Muscle Actin ◽

Converting Enzyme ◽

Hypoxic Conditions

Pulmonary veins show greater sensitivity to endothelin (ET)-1-induced vasoconstriction than pulmonary arteries, and remodeling was observed in pulmonary veins under hypoxic conditions. We examined, using an immunohistochemical method, the expression of Big ET-1, ET-converting enzyme (ECE), and ETA and ETB receptors in rat pulmonary veins under normoxic and hypoxic conditions. In control rats, Big ET-1 and ECE were coexpressed in the intima and media of the pulmonary veins, with an even distribution along the axial pathway. ETA and ETB receptors were expressed in the pulmonary veins, with a predominant distribution in the proximal segments. The expression of Big ET-1 was more abundant in the pulmonary veins than in the pulmonary arteries. After exposure to hypoxia for 7 or 14 days, the expression of Big ET-1, ECE, and ET receptors increased in small pulmonary veins. Increases in the medial thickness, wall thickness, and immunoreactivity for α-smooth muscle actin were also observed in the small pulmonary veins under hypoxic conditions. The upregulation of ET-1 and ET receptors in the small pulmonary veins is associated with vascular remodeling, which may lead to the development of hypoxic pulmonary hypertension.

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Regulation of soluble guanylyl cyclase-α1 expression in chronic hypoxia-induced pulmonary hypertension: role of NFATc3 and HuR

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00060.2009 ◽

2009 ◽

Vol 297 (3) ◽

pp. L475-L486 ◽

Cited By ~ 21

Author(s):

Sergio de Frutos ◽

Carlos H. Nitta ◽

Elizabeth Caldwell ◽

Jessica Friedman ◽

Laura V. González Bosc

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Smooth Muscle Cells ◽

Guanylyl Cyclase ◽

Chronic Hypoxia ◽

Pulmonary Arteries ◽

Soluble Guanylyl Cyclase ◽

Muscle Cells ◽

Pulmonary Artery Smooth Muscle

The nitric oxide/soluble guanylyl cyclase (sGC) signal transduction pathway plays an important role in smooth muscle relaxation and phenotypic regulation. However, the transcriptional regulation of sGC gene expression is largely unknown. It has been shown that sGC expression increases in pulmonary arteries from chronic hypoxia-induced pulmonary hypertensive animals. Since the transcription factor NFATc3 is required for the upregulation of the smooth muscle hypertrophic/differentiation marker α-actin in pulmonary artery smooth muscle cells from chronically hypoxic mice, we hypothesized that NFATc3 is required for the regulation of sGC-α1 expression during chronic hypoxia. Exposure to chronic hypoxia for 2 days induced a decrease in sGC-α1 expression in mouse pulmonary arteries. This reduction was independent of NFATc3 but mediated by nuclear accumulation of the mRNA-stabilizing protein human antigen R (HuR). Consistent with our hypothesis, chronic hypoxia (21 days) upregulated pulmonary artery sGC-α1 expression, bringing it back to the level of the normoxic controls. This response was prevented in NFATc3 knockout and cyclosporin (calcineurin/NFATc inhibitor)-treated mice. Furthermore, we identified effective binding sites for NFATc in the mouse sGC-α1 promoter. Activation of NFATc3 increased sGC-α1 promoter activity in human embryonic derived kidney cells, rat aortic-derived smooth muscle cells, and human pulmonary artery smooth muscle cells. Our results suggest that NFATc3 and HuR are important regulators of sGC-α1 expression in pulmonary vascular smooth muscle cells during chronic hypoxia-induced pulmonary hypertension.

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Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00114.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. L367-L374 ◽

Cited By ~ 61

Author(s):

Ioana R. Preston ◽

Nicholas S. Hill ◽

Rod R. Warburton ◽

Barry L. Fanburg

Keyword(s):

Endothelial Cells ◽

Pulmonary Hypertension ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Protein Expression ◽

Pulmonary Arteries ◽

Mek Inhibitor ◽

Gene And Protein Expression ◽

12 Lipoxygenase

The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism stimulates cell growth and metastasis of various cancer cells and the 12-LO metabolite, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], enhances proliferation of aortic smooth muscle cells (SMCs). However, pulmonary vascular effects of 12-LO have not been previously studied. We sought evidence for a role of 12-LO and 12(S)-HETE in the development of hypoxia-induced pulmonary hypertension. We found that 12-LO gene and protein expression is elevated in lung homogenates of rats exposed to chronic hypoxia. Immunohistochemical staining with a 12-LO antibody revealed intense staining in endothelial cells of large pulmonary arteries, SMCs (and possibly endothelial cells) of medium and small-size pulmonary arteries and in alveolar walls of hypoxic lungs. 12-LO protein expression was increased in hypoxic cultured rat pulmonary artery SMCs. 12(S)-HETE at concentrations as low as 10−5 μM stimulated proliferation of pulmonary artery SMCs. 12(S)-HETE induced ERK 1/ERK 2 phosphorylation but had no effect on p38 kinase expression as assessed by Western blotting. 12(S)-HETE-stimulated SMC proliferation was blocked by the MEK inhibitor PD-98059, but not by the p38 MAPK inhibitor SB-202190. Hypoxia (3%)-stimulated pulmonary artery SMC proliferation was blocked by both U0126, a MEK inhibitor, and baicalein, an inhibitor of 12-LO. We conclude that 12-LO and its product, 12(S)-HETE, are important intermediates in hypoxia-induced pulmonary artery SMC proliferation and may participate in hypoxia-induced pulmonary hypertension.

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Reexpression of caveolin-1 in endothelium rescues the vascular, cardiac, and pulmonary defects in global caveolin-1 knockout mice

Journal of Experimental Medicine ◽

10.1084/jem.20062340 ◽

2007 ◽

Vol 204 (10) ◽

pp. 2373-2382 ◽

Cited By ~ 163

Author(s):

Takahisa Murata ◽

Michelle I. Lin ◽

Yan Huang ◽

Jun Yu ◽

Phillip Michael Bauer ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Epithelial Cells ◽

Pulmonary Arteries ◽

Mitogen Activated Protein Kinase ◽

No Production ◽

Smooth Muscle Contractility ◽

Caveolin 1 ◽

Multiple Phenotypes ◽

Mitogen Activated Protein

Caveolin-1 (Cav-1) is the principal structural component of caveolae organelles in smooth muscle cells, adipocytes, fibroblasts, epithelial cells, and endothelial cells (ECs). Cav-1–deficient (Cav-1 knockout [KO]) mice are viable and show increases of nitric oxide (NO) production in vasculature, cardiomyopathy, and pulmonary dysfunction. In this study, we generated EC-specific Cav-1–reconstituted (Cav-1 RC) mice and reexamined vascular, cardiac, and pulmonary phenotypes. Cav-1 KO pulmonary arteries had decreased smooth muscle contractility and increased endothelial NO synthase activation and hypotension; the latter two effects were rescued completely in Cav-1 RC mice. Cav-1 KO mice exhibited myocardial hypertrophy, pulmonary hypertension, and alveolar cell hyperproliferation caused by constitutive activation of p42/44 mitogen-activated protein kinase and Akt. Interestingly, in Cav-1 RC mice, cardiac hypertrophy and pulmonary hypertension were completely rescued, whereas alveolar hyperplasia was partially recovered because of the lack of rescue of Cav-1 in bronchiolar epithelial cells. These results provide clear physiological evidence supporting the important role of cell type–specific Cav-1 expression governing multiple phenotypes in the vasculature, heart, and lung.

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Model Difference in the Effect of Cilostazol on the Development of Experimental Pulmonary Hypertension in Rats

10.21203/rs.3.rs-228016/v1 ◽

2021 ◽

Author(s):

Toshikazu Ito ◽

Erquan Zhang ◽

Ayaka Omori ◽

Jane Kabwe ◽

Masako Kawai ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Protein Expression ◽

Lung Tissue ◽

Pulmonary Arteries ◽

Weight Ratio ◽

Mrna Levels ◽

Sprague Dawley ◽

Model Lung ◽

Phosphorylated Akt ◽

The Right

Abstract Background: Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats.Methods: Fifty-one male Sprague-Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60 mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. Mean PAP (mPAP), the right ventricle weight-to-left ventricle+septum weight ratio (RV/LV+S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed.Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB in lung tissue was measured by Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed.Results: mPAP [35.1±1.7 mmHg (MCT) (n=9) vs.16.6±0.7 (control) (n=9) (p<0.05); 29.1±1.5 mmHg (CH) (n=10) vs. 17.5±0.5 (control) (n=10) (p<0.05)], RV/LV+S [0.40±0.01 (MCT) (n=18) vs. 0.24±0.01 (control) (n=10) (p<0.05); 0.41±0.03 (CH) (n=13) vs. 0.27±0.06 (control) (n=10) (p<0.05)], and %Muscularization and %MWT were increased by MCT injection and CH exposure. CLZ significantly attenuated these changes in the MCT model [mPAP 25.1±1.1 mmHg (n=11) (p<0.05), RV/LV+S 0.30±0.01 (n=14) (p<0.05)]. In contrast, these CLZ effects were not observed in the CH model. Lung eNOS protein expression was unchanged in the MCT model and high in the CH model. Lung protein expression of AKT, phosphorylated AKT, and IκB was downregulated by MCT, which was attenuated by CLZ; the CH model did not change these proteins. Lung MCP-1 mRNA levels were increased in MCT rats but not CH rats.Conclusion: We found model differences in the effect of CLZ on PH development. CLZ might have a preventable effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might be dependent on PH etiology.

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Nrf2 Activation Attenuates Hemolysis but Promotes Pulmonary Vascular Dysfunction in Sickle Mice

Blood ◽

10.1182/blood.v128.22.1296.1296 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1296-1296

Author(s):

Chibueze A. Ihunnah ◽

Samit Ghosh ◽

Scott A. Hahn ◽

Adam C Straub ◽

Solomon F Ofori-Acquah

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Smooth Muscle Cells ◽

Cardiovascular Events ◽

Vascular Dysfunction ◽

Pulmonary Arteries ◽

Intravascular Hemolysis ◽

Nrf2 Activation ◽

Nrf2 Activator

Abstract Nuclear factor erythroid 2-related factor 2 (Nrf2) is the major transcription factor that coordinates the body's antioxidant and cytoprotective defense against a variety of toxins. Several Nrf2 activators can reactivate gamma globin gene expression and augment fetal hemoglobin production. More recently, genetic and pharmacologic evidence have shown that Nrf2 activation can specifically mitigate the severity of hemolytic anemia, and systemic and local inflammation in transgenic sickle cell disease (SCD) mice. Based on these encouraging results Nrf2 activation has emerged as an attractive therapeutic strategy in SCD. However, the BEACON trial of the Nrf2 activator CDDO-Methyl Ester (CDDO-Me) showed that this therapeutic approach can cause adverse cardiovascular events in patients with chronic kidney disease with comorbid diabetes. Hitherto, the efficacy-toxicity profile generated by individual Nrf2 activating drugs has not been investigated in SCD. There are hundreds of synthetic and naturally occurring Nrf2 activating compounds, and each class of Nrf2 activating compound has a unique pharmacokinetic, pharmacodynamic, toxicokinetic and toxicodynamic profile. We have recently demonstrated that intravascular hemolysis deteriorates with aging in transgenic sickle (SS) mice in a process that can be mitigated by the Nrf2 activator 3H-1,2-dithiole-3-thione (D3T) (Ghosh et al., JCI Insight, 2016). In this study, an in vitro screen of five Nrf2 activating compounds revealed CDDO-Me to be the most potent inducer of cytoprotective enzymes in human pulmonary microvascular endothelial cells. Thus, we performed a long-term prophylactic CDDO-Me treatment of SS mice and examined the effect of the drug on intravascular hemolysis and vascular dysfunction. A cohort of newly weaned SS mice aged ~4 weeks were randomly assigned to receive CDDO-Me (20µmoles/kg/TIW, n=6) or Vehicle (DMSO/TIW, n=10) by oral gavage for 4 months. After the treatment, the total hemoglobin increased by 10% in the CDDO-Me group while it decreased by 5% in the vehicle-treated group (p<0.05). Plasma concentration of VCAM-1 increased in both groups compared to their respective baseline (vehicle p<0.001; CDDO-Me p<0.05). The lack of impact on VCAM-1 by CDDO-Me was contrary to our results with D3T (Ghosh et al., JCI Insight, 2016). To examine this further, we performed vascular reactivity studies on isolated pulmonary arteries. Second order pulmonary arteries were isolated, cut into 2mm rings, and mounted using 40 μm wire. Rings were set at a resting tension equivalent to 100 mmHg transmural pressure. Cumulative dose response curves of endothelin-1 (100 pM-10 nM) and acetylcholine (10nM-100 μM) were used to study vasoconstriction and vasodilation, respectively. Pulmonary arteries isolated from the CDDO-Me treated SS mice showed a 15% reduction in acetylcholine stimulated vasodilation compared to the arteries isolated from the vehicle treated littermates (vehicle n=5, CDDO-Me n=5; p<0.001). In vitro studies of rat smooth muscle cells revealed significant up-regulation of endothelin receptor subtype A (ETA) mRNA by CDDO-Me (p < 0.01, n=6). We obtained similar results of increased ETA expression in rat smooth muscle cells treated with another Nrf2 activator, Dimethyl Fumarate (DMF) (p < 0.01, n=6). Upregulation of endothelin or the ETA is frequently found in pulmonary hypertension. The hypertensive phenotype that we report here in SS mice treated with CDDO-Me is consistent with the adverse cardiovascular events found in the BEACON trial. Together our results show that while CDDO-Me can stabilize and potentially improve hemolytic anemia in SCD, this drug and potentially other Nrf2 activators may promote the development of pulmonary hypertension, which is a major adult complication of SCD. Disclosures No relevant conflicts of interest to declare.

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Severe asthma is associated with a remodeling of the pulmonary arteries in horses

10.1101/2020.04.15.042903 ◽

2020 ◽

Author(s):

Serena Ceriotti ◽

Michela Bullone ◽

Mathilde Leclere ◽

Francesco Ferrucci ◽

Jean-Pierre Lavoie

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Muscle Mass ◽

Pulmonary Arteries ◽

Chronic Obstructive ◽

Corticosteroid Administration ◽

Wall Area ◽

Hypoxic Vasoconstriction ◽

Equine Asthma

AbstractPulmonary hypertension and cor pulmonale are complications of severe equine asthma, as a consequence of pulmonary hypoxic vasoconstriction. However, as pulmonary hypertension is only partially reversible by oxygen administration, other etiological factors are likely involved. In human chronic obstructive pulmonary disease, pulmonary artery remodeling contributes to the development of pulmonary hypertension. In rodent models, pulmonary vascular remodeling is present as a consequence of allergic airway inflammation. The present study investigated the presence of remodeling of the pulmonary arteries in severe equine asthma, its distribution throughout the lungs, and its reversibility following long-term antigen avoidance strategies and inhaled corticosteroid administration. Using histomorphometry, the total wall area of pulmonary arteries from different regions of the lung of asthmatic horses and controls was measured. The smooth muscle mass of pulmonary arteries was also estimated on lung sections stained for α-smooth muscle actin. Reversibility of vascular changes in asthmatic horses was assessed after 1 year of antigen avoidance alone or treatment with inhaled fluticasone. Pulmonary arteries showed increased wall area in apical and caudodorsal lung regions of asthmatic horses in both exacerbation and remission. The pulmonary arteries smooth muscle mass was similarly increased. Both treatments reversed the increase in wall area. However, normalization of the vascular smooth muscle mass was observed only after treatment with antigen avoidance, but not with fluticasone. In conclusion, severe equine asthma is associated with remodeling of the pulmonary arteries consisting in an increased smooth muscle mass. The resulting narrowing of the artery lumen could enhance hypoxic vasoconstriction, contributing to pulmonary hypertension. Vascular smooth muscle mass normalization is better achieved by antigen avoidance than with inhaled corticosteroids.

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Pulmonary hypertension is attenuated and ventilation-perfusion matching is maintained during chronic hypoxia in deer mice native to high altitude

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00282.2020 ◽

2021 ◽

Author(s):

Claire M. West ◽

Oliver H. Wearing ◽

Rod G. Rhem ◽

Graham R. Scott

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Right Ventricle ◽

High Altitude ◽

Chronic Hypoxia ◽

Pulmonary Arteries ◽

Deer Mice ◽

Maladaptive Response ◽

Ventricle Hypertrophy ◽

Right Ventricle Hypertrophy

Hypoxia at high altitude can constrain metabolism and performance, and can elicit physiological adjustments that are deleterious to health and fitness. Hypoxic pulmonary hypertension is a particularly serious and maladaptive response to chronic hypoxia, which results from vasoconstriction and pathological remodeling of pulmonary arteries, and can lead to pulmonary edema and right ventricle hypertrophy. We investigated whether deer mice (Peromyscus maniculatus) native to high altitude have attenuated this maladaptive response to chronic hypoxia, and whether evolved changes or hypoxia-induced plasticity in pulmonary vasculature might impact ventilation-perfusion (V-Q) matching in chronic hypoxia. Deer mouse populations from both high and low altitudes were born and raised to adulthood in captivity at sea level, and various aspects of lung function were measured before and after exposure to chronic hypoxia (12 kPa O2, simulating the O2 pressure at 4300 m) for 6-8 weeks. In lowlanders, chronic hypoxia increased right ventricle systolic pressure (RVSP) from 14 to 19 mmHg (P = 0.001), in association with thickening of smooth muscle in pulmonary arteries and right ventricle hypertrophy. Chronic hypoxia also impaired V-Q matching in lowlanders (measured at rest using SPECT-CT imaging), as reflected by increased log SD of the perfusion distribution (log SDQ) from 0.55 to 0.86 (P = 0.031). In highlanders, chronic hypoxia had attenuated effects on RVSP and no effects on smooth muscle thickness, right ventricle mass, or V-Q matching. Therefore, evolved changes in lung function help attenuate maladaptive plasticity and contribute to hypoxia tolerance in high-altitude deer mice.

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