scholarly journals Beyond Thrombosis: the Role of Platelets in Pulmonary Hypertension

2020 ◽  
Vol 2 (4) ◽  
pp. 243-271
Author(s):  
Salina Nicoleau ◽  
Beata Wojciak-Stothard
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Pressure ◽  
Right Heart Failure ◽  
Inflammatory Cells ◽  
The Past ◽  
Current State ◽  
Wide Range ◽  
Pulmonary Arterial

Pulmonary Hypertension (PH) is a multifactorial and lethal disease, characterised by elevated pulmonary arterial pressure and progressive right heart failure. PH pathobiology rests on four pillars: vascular remodelling, vasoconstriction, inflammation and thrombosis. While vascular and inflammatory cells have been the focus of PH research over the past decades, platelets have received relatively less attention, despite their associations with key pathophysiological processes of the disease. Platelets contain a wide range of vasoactive, inflammatory and pro-thrombotic mediators, likely to promote PH development and progression. There is currently no cure for PH, and platelet-associated pathways may help identify new therapeutic strategies. This review summarises available evidence on the role of platelets in different forms of PH, and comments on the current state of platelet-targeting therapies. It also describes the latest advances in the in vitro technologies that enable exploration of platelet function under dynamic and physiologically relevant conditions. Doi: 10.28991/SciMedJ-2020-0204-7 Full Text: PDF

L-Arginine, a precursor of EDRF in vitro, produces pulmonary vasodilation in lambs

1991 ◽  
Vol 261 (5) ◽  
pp. H1563-H1569 ◽  
Author(s):  
J. R. Fineman ◽  
R. Chang ◽  
S. J. Soifer
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Phosphodiesterase Inhibitor ◽  
Hemodynamic Effects ◽  
Synthesis Inhibitor ◽  
Pulmonary Vasodilation ◽  
Pulmonary Arterial ◽  
Rate Limiting

There is increasing evidence that resting pulmonary vascular tone is mediated in part by the release of endothelium-derived relaxing factors (EDRF). Because L-arginine may be a precursor for EDRF synthesis, we studied the pulmonary vasodilating effects of L-arginine at rest and during pulmonary hypertension in 16 intact newborn lambs. At rest, the intravenous infusions of L-arginine (150 mg/kg) had no hemodynamic effects. However, during pulmonary hypertension induced by hypoxia or the infusion of U-46619 (a thromboxane A2 mimic), L-arginine decreased pulmonary arterial pressure by 22 and 27%, respectively (P less than 0.05). The decrease in pulmonary arterial pressure produced by L-arginine was blocked by methylene blue, a guanylate cyclase inhibitor, and augmented by Zapranast, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor (-17.9 vs. -31.2%, P less than 0.05). In addition, L-arginine partially reversed the pulmonary hypertension induced by N omega-nitro-L-arginine, a competitive EDRF synthesis inhibitor, but D-arginine had no hemodynamic effects. This study suggests that L-arginine produces pulmonary vasodilation by increasing cGMP concentrations, supporting the in vitro hypothesis that L-arginine is a precursor for EDRF synthesis, whose availability may become rate limiting during pulmonary hypertension.

scholarly journals Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension

2020 ◽  
pp. 1902061
Author(s):  
David Macias ◽  
Stephen Moore ◽  
Alexi Crosby ◽  
Mark Southwood ◽  
Xinlin Du ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Target Genes ◽  
Right Heart Failure ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary Arterial Hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant HIF2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from IPAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyper-proliferative phenotype and over-active arginase activity in blood outgrowth endothelial cells from IPAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

The role of pulmonary intravascular macrophages in porcine reproductive and respiratory syndrome virus infection

2000 ◽  
Vol 1 (2) ◽  
pp. 95-102 ◽  
Author(s):  
Roongroje Thanawongnuwech ◽  
Patrick G. Halbur ◽  
Eileen L. Thacker
Keyword(s):  
Virus Titer ◽  
Respiratory Syndrome Virus ◽  
The Past ◽  
Current State ◽  
Viral Particles ◽  
Increased Susceptibility ◽  
Pulmonary Intravascular Macrophages

AbstractThe objective of this article is to summarize the current state of knowledge of the complex interaction of porcine reproductive and respiratory syndrome virus (PRRSV) and porcine pulmonary intravascular macrophages (PIMs). PIMs play an important role in pulmonary surveillance, and in the past few years we have investigated their role in PRRSV infection. PRRSV antigens and nucleic acids have been demonstrated in PIMs bothin vitroandin vivo. Examination of cultured PIMs infected with PRRSV revealed the accumulation of viral particles in the smooth-walled vesicles. PRRSV-infected PIMsin vitroyielded a virus titer similar to pulmonary alveolar macrophages. PRRSV infection induces either apoptosis or cell lysis of PIMs. Thein vitrobactericidal activity of PRRSV-infected PIMs is significantly decreased. Phagocytic activity of PIMs, as measured by pulmonary copper clearance, is significantly decreased in PRRSV-infected pigs. This evidence supports the hypothesis that PRRSV-induced damage to PIMs results in increased susceptibility to bacteremic diseases. Recent studies with PRRSV andStreptococcus suiscoinfection confirmed that PRRSV predisposes pigs toS. suisinfection and bacteremia. These results could explain the increase in bacterial respiratory diseases and septicemias observed in PRRSV-infected pigs.

Loss of endothelium-dependent vasodilation in the pulmonary vessels of sheep after prolonged endotoxin

1994 ◽  
Vol 76 (1) ◽  
pp. 361-369 ◽  
Author(s):  
J. A. Spath ◽  
P. J. Sloane ◽  
M. H. Gee ◽  
K. H. Albertine
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Prolonged Exposure ◽  
Pulmonary Arterial Pressure ◽  
Necrosis Factor Alpha ◽  
Pulmonary Vessels ◽  
Endotoxin Infusion ◽  
Pulmonary Arterial ◽  
Endothelium Dependent Relaxation

We examined the hemodynamic response of awake sheep to prolonged endotoxin infusion (10 ng.kg-1 x min-1 for 12 h) and the in vitro endothelium-dependent relaxation of pulmonary arterial vessels excised 12 h after the end of endotoxin infusion to determine whether the development of pulmonary hypertension after endotoxin is associated with loss of endothelium-dependent relaxation. In seven of nine sheep, there was a maintained increase (4–68% of baseline) in pulmonary arterial pressure 24 h after the beginning of endotoxin infusion. The greater the increase in pulmonary arterial pressure in vivo, the greater was the in vitro deficit in endothelium-dependent relaxation of the pulmonary vessels. The maximum in vitro vessel dilation was 59% for pulmonary artery rings isolated from sheep without a sustained increase in pulmonary arterial pressure 24 h after endotoxin. Prolonged endotoxin infusion did not alter the in vitro response of pulmonary arterial vessels to KCl or 10(-5) M norepinephrine. Force development, response to 10(-5) M norepinephrine, and vasodilation in response to acetylcholine were also not altered in pulmonary vessels taken from control sheep and exposed in vitro to tumor necrosis factor-alpha (400 U/ml). Our results suggest that loss of endothelium-dependent relaxation in pulmonary vessels supports the sustained pulmonary hypertension that develops after prolonged exposure to endotoxin.

Abstract 16629: Endothelial Caveolin-1-trpv4 Regulation of Pulmonary Arterial Pressure and Impairment in Pulmonary Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zdravka Daneva ◽  
Corina Marziano ◽  
Matteo Ottolini ◽  
YEN LIN CHEN ◽  
Kwangseok Hong ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Mouse Models ◽  
Pulmonary Arterial Pressure ◽  
Scaffolding Protein ◽  
Channel Activity ◽  
Caveolin 1 ◽  
Pulmonary Arterial ◽  
Trpv4 Channel

Background: Pulmonary hypertension (PH) is a degenerative disorder that is characterized by elevated vascular resistance and pulmonary arterial pressure (PAP). Endothelial transient receptor potential vanilloid 4 (TRPV4 EC ) ion channels represent an important Ca 2+ influx signaling mechanism that promotes vasodilation of small pulmonary arteries (PAs). Scaffolding protein caveolin-1 (Cav-1) has been shown to precipitate with TRPV4 channels in pulmonary endothelial cells in culture. Hypothesis: We hypothesized that the endothelial Cav-1-TRPV4 channel signaling in small PAs lowers PAP, and is impaired in PH. Methods: Inducible endothelium-specific KO mice for TRPV4 channel or Cav-1 were used to study the role of Cav-1-TRPV4 signaling in the regulation of resting PAP. Endothelium-specific P2Y2 receptor KO mice were used to test if Cav-1 provides a signaling scaffold for purinergic activation of TRPV4 EC channels. Endothelial Cav-1-TRPV4 signaling was assessed in PAs from two PH mouse models and PH patients. The role of NADPH oxidase (NOX1)- and inducible nitric oxide synthase (iNOS)-mediated peroxynitrite (PN), an oxidant molecule, in impairing Cav-1-TRPV4 signaling in PH was evaluated using NOX1-/- and iNOS-/- mice and pharmacological inhibitors. Results: We show that endothelial Cav-1-TRPV4 signaling in small PAs lowers resting PAP, and protects against the pathogenesis of PH. Endothelial Cav-1 provides a signaling scaffold for the activation of TRPV4 channels by endogenous purinergic receptor signaling. Moreover, TRPV4 EC channel activity and Cav-1-TRPV4 signaling are impaired in small PAs from two mouse models of PH and PH patients. Elevated levels of NOX1 and iNOS enzymes in caveolae resulted in PN formation close to Cav-1 in PH. Elevated PN targeted Cav-1 to lower Cav-1-TRPV4 signaling, thereby contributing to impaired vasodilation and increased PAP. Pharmacological inhibition of NOX1, iNOS, or PN rescued TRPV4 EC channel activity and vasodilation in PH. Conclusion: This study provides novel evidence that endothelial Cav-1-TRPV4 signaling lowers PAP and is impaired in PH. Inhibiting NOX1 or iNOS activity, or lowering endothelial PN levels may represent a novel strategy for restoring TRPV4 EC channel activity, vasodilation, and PAP.

Cyclooxygenase pathway mediates lung injury induced by phorbol and platelets

1991 ◽  
Vol 70 (6) ◽  
pp. 2417-2421 ◽  
Author(s):  
D. Wang ◽  
C. L. Chou ◽  
K. Hsu ◽  
H. I. Chen
Keyword(s):  
Lung Injury ◽  
Pulmonary Arterial Pressure ◽  
Nordihydroguaiaretic Acid ◽  
Thromboxane B2 ◽  
Myristate Acetate ◽  
Lung Weight ◽  
Edema Formation ◽  
Pulmonary Arterial

The role of platelets in lung injury has not been well defined. In the present study of isolated perfused rat lungs, phorbol myristate acetate (PMA; 0.15 microgram/ml) or platelets (6.7 X 10(4)/ml) alone did not discernibly change the pulmonary arterial pressure (PAP) or lung weight (LW). However, the combination of platelets and PMA drastically increased the PAP and LW (delta PAP 26.2 +/- 1.0 mmHg, delta LW 2.7 +/- 0.4 g). delta PAP was positively correlated with the increase in thromboxane B2 produced by infusion of platelets and PMA (thromboxane B2 = 35.6 + 0.97 delta PAP, r = 0.67, P less than 0.01). The hypertension and edema formation induced by PMA and platelets were strongly attenuated by indomethacin, an inhibitor of platelet cyclooxygenase (delta PAP 5.6 +/- 2.0 mmHg, P less than 0.001; delta LW 0.0 +/- 0.1 g, P less than 0.001), and by imidazole, an inhibitor of thromboxane A2 synthase (PAP 8.0 +/- 2.5 mmHg, P less than 0.001; LW 0.0 +/- 0.3 g, P less than 0.01). Inactivation of platelet lipoxygenase with nordihydroguaiaretic acid mildly depressed pulmonary pressure but did not affect delta LW (delta PAP 18.9 +/- 1.6 mmHg, P less than 0.05; delta LW 3.1 +/- 0.3 g, P greater than 0.05). In vitro experiments showed that the capacity of platelets to release oxygen radicals was only 2.6% of that found for granulocytes. These results suggest that platelets may be activated by PMA to increase PAP and vascular permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Depletion of Alveolar Macrophages Attenuates Hypoxic Pulmonary Hypertension but not Hypoxia-Induced Increase in Serum Concentration of MCP-1

2016 ◽  
pp. 763-768 ◽  
Author(s):  
M. ŽALOUDÍKOVÁ ◽  
R. VYTÁŠEK ◽  
O. VAJNEROVÁ ◽  
O. HNILIČKOVÁ ◽  
M. VÍZEK ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Alveolar Macrophages ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Hypertension ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Mean Pulmonary Arterial Pressure ◽  
Selective Elimination ◽  
Pulmonary Arterial

Exposure to hypoxia, leading to hypoxic pulmonary hypertension (HPH), is associated with activation of alveolar macrophages (AM). However, it remains unclear how AM participate in this process. There are studies which imply that the AM product monocyte chemoattractant protein-1 (MCP-1) plays an important role. Thus we tested: 1. if the selective elimination of AM attenuates HPH in rats, 2. the correlation of MCP-1 plasmatic concentrations with the presence and absence of AM during exposure to hypoxia, 3. the direct influence of hypoxia on MCP-1 production in isolated AM. We found that experimental depletion of AM attenuated the chronic hypoxia-induced increase in mean pulmonary arterial pressure, but did not affect the serum MCP-1 concentrations. Furthermore, the MCP-1 production by AM in vitro was unaffected by hypoxia. Thus we conclude that AM play a significant role in the mechanism of HPH, but MCP-1 release from these cells is most likely not involved in this process. The increase of MCP-1 accompanying the development of HPH probably originates from other sources than AM.

Effect of leukopenia on pulmonary hypertension after heparin-protamine in pigs

1992 ◽  
Vol 73 (1) ◽  
pp. 44-49 ◽  
Author(s):  
H. Habazettl ◽  
P. F. Conzen ◽  
B. Vollmar ◽  
E. Yekebas ◽  
K. Peter
Keyword(s):  
Pulmonary Hypertension ◽  
Thromboxane A2 ◽  
Thromboxane B2 ◽  
Control Group ◽  
Mean Pulmonary Arterial Pressure ◽  
Leukocyte Counts ◽  
Pulmonary Arterial ◽  
Heparin Neutralization

Heparin neutralization by protamine after cardiac surgery and cardiopulmonary bypass may be associated with complement activation, transient leukopenia, thromboxane A2 release, and severe pulmonary hypertension. The role of leukocytes in the heparin-protamine reaction was studied in leukopenic pigs (n = 9) and a control group (n = 8). Leukopenia was induced by pretreatment with cyclophosphamide (30 mg.kg-1.day-1) for 6–7 days. During general anesthesia and after catheterization, baseline recordings of hemodynamics were performed and blood samples were withdrawn. Heparin (250 IU/kg) was injected and measurements were repeated after 10 min. Protamine sulfate (100 mg) was then infused over 2 min and measurements were performed after 2, 5, and 15 min. Prostanoid concentrations were measured by radioimmunoassays. In additional in vitro experiments, the release of thromboxane B2 from washed platelets and leukocytes after heparin-protamine stimulation was measured. Pretreatment with cyclophosphamide reduced leukocyte counts by 95.5% and the number of neutrophils by greater than 99.9%. Protamine infusion increased mean pulmonary arterial pressure by 74 and 46% and pulmonary vascular resistance by 185 and 384% in control and leukopenic animals, respectively. Thromboxane B2 concentrations increased in both groups. Stimulation by heparin, protamine, or heparin and protamine in sequence did not induce any thromboxane A2 release from washed blood cells. It is concluded that leukocytes do not contribute to pulmonary hypertension after heparin-protamine.

Cold-induced pulmonary hypertension in cattle

1978 ◽  
Vol 45 (3) ◽  
pp. 469-473 ◽  
Author(s):  
D. H. Will ◽  
I. F. McMurtry ◽  
J. T. Reeves ◽  
R. F. Grover
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Right Heart Failure ◽  
Early Spring ◽  
Oxygen Breathing ◽  
Pulmonary Arterial ◽  
Lung Vessels

The frequency with which cattle develop right-heart failure during the winter at high altitude suggested that cold might contribute to hypoxic pulmonary hypertension. Indeed in a preliminary study conducted out-of-doors during early Spring, two calves with known hyperreactive pulmonary vessels showed elevated pulmonary arterial pressures attributed to their prior exposure to nighttime cold (-5 degrees C). In a second study five hyperreactive calves had increases in mean pulmonary arterial pressure from 29 to 45 Torr (+ 55%) during 48 h of exposure to cold (0 to -5 degrees C) in a climatic chamber. Three calves with less reactive lung vessels increased their pressures from 25 to 36 Torr (+ 44%). In a more complete study, six calves selected as potential hyperresponders showed increases in pulmonary arterial pressure (+ 60%), blood flow (+ 18%), and vascular resistance (+ 38%) during 48 h of cold exposure. Arterial PO2 decreased (-10 Torr) and PCO2 rose (+6 Torr) suggesting hypoventilation. Oxygen breathing returned pulmonary pressures and resistance to near control values, suggesting that cold had induced a hypoxic pulmonary vasoconstriction and an increased blood flow. Thus, a cold produced pulmonary hypertension in cattle at the modest altitude of 1,524 m and the pressor responses were greater in calves with more reactive lung vessels.

Protection from pulmonary hypertension with an orally active endothelin receptor antagonist in hypoxic rats

1995 ◽  
Vol 268 (2) ◽  
pp. H828-H835 ◽  
Author(s):  
S. Eddahibi ◽  
B. Raffestin ◽  
M. Clozel ◽  
M. Levame ◽  
S. Adnot
Keyword(s):  
Pulmonary Hypertension ◽  
Ventricular Hypertrophy ◽  
Vascular Reactivity ◽  
Potential Role ◽  
Pulmonary Arterial Pressure ◽  
Pressor Response ◽  
Endothelin Receptor ◽  
Pulmonary Arterial ◽  
Orally Active

The aim of this study was to investigate the potential role of endothelin (ET) in the development of chronic hypoxic pulmonary hypertension. Pulmonary vascular reactivity to ET-1 was first examined in isolated perfused lungs from normoxic and chronically hypoxic rats in the presence of bosentan, a new nonpeptide mixed antagonist of ETA and ETB receptors. The effect of chronic treatment with bosentan was then examined in rats that were exposed to chronic hypoxia and developed pulmonary hypertension. In lungs from normoxic rats, bosentan (10(-5) M) abolished the vasodilator responses to ET-1 (10(-10) M) or to the ETB-selective agonist IRL-1620 (10(-10) M) and attenuated the vasoconstrictor responses to 10(-9) M ET-1 (from 8.7 +/- 0.7 to 1.8 +/- 0.3 mmHg, P < 0.01) or 10(-9) M IRL-1620 (from 1.5 +/- 0.4 to 0.4 +/- 0.1 mmHg, P < 0.05). In lungs from chronically hypoxic rats, the pressor response to 3 x 10(-10) M ET-1 was abolished by bosentan and partially reduced by the selective ETA antagonist BQ-123. In conscious rats previously exposed to hypoxia for 15 days, pretreatment with bosentan (100 mg.kg-1.day-1 by gavage) for 3 days attenuated the increase in systemic arterial pressures and the concomitant decrease of cardiac output in response to an intravenous bolus of ET-1 (3 x 10(-10) M). In rats exposed to hypoxia for 15 days and simultaneously treated with bosentan, pulmonary arterial pressure was lower (P < 0.05) and right ventricular hypertrophy was less severe (P < 0.01) than in control hypoxic rats treated with vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

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