Academic literature on the topic 'Pulmonary arterial hyperreactivity'

PPHN, caused by perinatal hypoxia or inflammation, is characterized by an increased thromboxane-prostacyclin ratio and pulmonary vasoconstriction. We examined effects of hypoxia on myocyte thromboxane responsiveness. Myocytes from 3rd–6th generation pulmonary arteries of newborn piglets were grown to confluence and synchronized in contractile phenotype by serum deprivation. On the final 3 days of culture, myocytes were exposed to 10% O2 for 3 days; control myocytes from normoxic piglets were cultured in 21% O2. PPHN was induced in newborn piglets by 3-day hypoxic exposure (FiO2 0.10); pulmonary arterial myocytes from these animals were maintained in normoxia. Ca2+ mobilization to thromboxane mimetic U-46619 and ATP was quantified using fura-2 AM. Three-day hypoxic exposure in vitro results in increased basal [Ca2+]i, faster and heightened peak Ca2+ response, and decreased U-46619 EC50. These functional changes persist in myocytes exposed to hypoxia in vivo but cultured in 21% O2. Blockade of Ca2+ entry and store refilling do not alter peak U-46619 Ca2+ responses in hypoxic or normoxic myocytes. Blockade of ryanodine-sensitive or IP3-gated intracellular Ca2+ channels inhibits hypoxic augmentation of peak U-46619 response. Ca2+ response to ryanodine alone is undetectable; ATP-induced Ca2+ mobilization is unaltered by hypoxia, suggesting no independent increase in ryanodine-sensitive or IP3-linked intracellular Ca2+ pool mobilization. We conclude hypoxia has a priming effect on neonatal pulmonary arterial myocytes, resulting in increased resting Ca2+, thromboxane hypersensitivity, and hyperreactivity. We postulate that hypoxia increases agonist-induced TP-R-linked IP3 pathway activation. Myocyte thromboxane hyperresponsiveness persists in culture after removal from the initiating hypoxic stimulus, suggesting altered gene expression.

Since alterations in pulmonary hemodynamics may lead to airway hyperreactivity, the consequences of individual changes in pulmonary blood flow (Q̇p) and capillary pressure (Pc) on lung responsiveness were investigated. During maintenance of a steady-state Pc of 5, 10, or 15 mmHg ( groups 1–3), acute increases of Q̇p were generated in isolated, perfused rat lungs by simultaneous pulmonary arterial pressure elevation and venous pressure lowering. Conversely, at constant low ( groups 4 and 5) or high Q̇p ( groups 6 and 7), Pc was lowered or elevated by changing, in parallel, the pulmonary arterial and venous pressures. Pulmonary input impedance was measured under baseline conditions and during methacholine provocation (2–18 μg·kg−1·min−1), whereas the pulmonary hemodynamics were altered in accordance with the group allocation. The airway resistance and constant-phase parenchymal model parameters were identified from the pulmonary input impedance spectra. Increases of Q̇p at constant Pc had no effect on the basal lung mechanics, whereas they enhanced the lung reactivity to methacholine, particularly when high Pc was maintained [peak airway resistance increases of 299 ± 99% (SE) vs. 609 ± 217% at Q̇p levels of 5 and 10 ml/min, respectively, P < 0.05]. In contrast, the change of Pc at constant Q̇p slightly deteriorated the basal parenchymal mechanics without affecting the lung responsiveness. These findings suggest that increases in Q̇p per se may lead to the development of airway hyperreactivity. This phenomenon may contribute to the airway susceptibility under conditions associated with simultaneous elevations in pulmonary vascular pressures and Q̇p, such as exercise-induced asthma and the situation in children with congenital heart diseases.

Postobstructive pulmonary vasculopathy (POPV) was produced by chronic ligation (120 days) of the left main pulmonary artery of seven dogs. To explain the abnormal physiological changes found using arterial and venous occlusion (AVO) in POPV (J. Appl. Physiol. 69: 1022–1032, 1990), the light-microscopic morphology, morphometry (n = 5), and ultrastructure (n = 6) of ligated left lower lobes were compared with contralateral control right lower lobes. First, there was a proliferation of bronchial vessels around pulmonary vessels and airways to explain bronchial blood flow rates of 330 ml/min in left lower lobes. The walls of the bronchial vessels contained smooth muscle with minimal elastic tissue and prominent myoendothelial junctions. Second, focal bronchopulmonary anastomoses were seen in pulmonary arteries approximately equal to 100 microns diam, which is consistent with our conclusion that the major site of communication is at the precapillary level and suggests that the limit between arterial and middle segments defined by AVO may lie in arteries of approximately equal to 100 microns. Third, to explain the increased arterial resistance in POPV, the pulmonary arteries had an increased percent medial muscle thickness, peripheral muscularization, and focal intimal thickening but had no plexiform lesions. The ultrastructure of the arteries revealed new intimal cells and numerous myoendothelial junctions rarely found in controls. Capillaries and veins were only subtly altered. Fourth, the hyperreactivity of arteries to serotonin and of veins to histamine found using AVO was partially explained by the increased medial thickness and decreased diameter but may also be due to increased receptor concentration or related to the myoendothelial junctions. We conclude that most of the hemodynamic alterations in POPV are related to morphological abnormalities and that this model has clinical and experimental relevance in the study of bronchopulmonary vascular interactions.

The sticky platelet syndrome (SPS) is a common cause of both arterial and venous thrombosis, being a dominant autosomal disease with qualitative platelet alterations and familial occurrence. It is characterized by platelet hyperreactivity with increased platelet aggregability in response to low concentrations of platelet agonists: epinephrine, adenosine diphosphate, or both. The clinical manifestations involve venous or arterial thrombosis, recurrent pregnancy loss, and fetal growth retardation. To analyze the localization of the thrombotic episodes in a cohort of Mexican mestizo patients with SPS. Between 1992 and 2016, 86 Mexican mestizo patients with SPS as the single thrombophilic condition were prospectively identified; all of them had a history of thrombosis. There were 15 males and 71 females. The thrombotic episodes were arterial in 26 cases and venous in 60 (70%). Arterial thrombosis was mainly pulmonary thromboembolism, whereas venous thromboses were identified most frequently in the lower limbs. Mexican mestizo population with SPS is mainly female; the type I of the condition is the most frequent; both arterial and venous thrombosis can occur, and they are mainly pulmonary embolism and lower limbs venous thrombosis, respectively.

L’hypertension pulmonaire (HTP) est une maladie grave caractérisée par une augmentation de la pression artérielle pulmonaire moyenne supérieure à 20 mmHg au repos contre 14 mmHg chez un individu sain. Cette pathologie conduit à terme à une insuffisance cardiaque droite et au décès du patient. En l’absence de traitement curatif, l’identification de nouvelles cibles thérapeutiques est un enjeu majeur. Dans ce contexte, une meilleure compréhension du développement et de la progression de l’HTP est donc primordiale. Au laboratoire, une cible d’intérêt à l’étude est le facteur de croissance des nerfs ou NGF, surexprimé au niveau des artères pulmonaires dans l’HTP expérimentale et humaine, et jouant un rôle dans les trois caractéristiques majeures de l’HTP (inflammation, réactivité et remodelage artériels pulmonaires).Dans un premier temps, nous avons étudié les mécanismes activés dans l’HTP pouvant contribuer à l’augmentation d’expression artérielle pulmonaire du NGF. Nous avons ainsi montré que des cytokines pro-inflammatoires augmentées dans l’HTP telles que l’interleukine-1β (IL-1β) et le Tumor necrosis factor-α mais aussi qu’un stress oxydant entrainaient une augmentation de l’expression et de la sécrétion de NGF par les cellules endothéliales -CE- et les cellules musculaires lisses -CML-artérielles pulmonaires. Nous avons montré que cette sécrétion faisait intervenir le Transforming growth factorβ1, qui, sécrété par les CE et les CML, agit alors de manière autocrine sur ces mêmes cellules pour stimuler la sécrétion de NGF.Dans un deuxième temps, nous avons étudié le rôle du NGF dans deux caractéristiques physiopathologiques de l’HTP : l’hyperréactivité et l’inflammation artérielles pulmonaires.Tout d’abord, nous avons montré qu’un traitement chronique des artères pulmonaires par le NGF (24h) induit une hyperréactivité artérielle pulmonaire en augmentant l’activité des jonctions communicantes constituées de connexine-43. En parallèle, nos résultats montrent qu’un traitement plus court des artères pulmonaires par le NGF (1h) induit également une hyperréactivité artérielle pulmonaire, mais en faisant intervenir d’autres mécanismes connexine-43 indépendants, en particulier une dérégulation de la signalisation calcique intracellulaire ainsi qu’une sensibilisation de l’appareil contractile.Par ailleurs, nous avons également étudié le lien entre NGF et inflammation dans l’HTP. In vivo dans un modèle d’HTP chez le rat, nous avons montré qu‘un traitement préventif avec des anticorps bloquants anti-NGF réduit l’infiltration de monocytes/macrophages et l’expression des protéines des inflammasomes dans les artères pulmonaires, et réduit également les taux circulants et pulmonaires d’IL-1β. In vitro, nos résultats montrent que le NGF est un facteur chimioattracteur des monocytes et que l’IL-1β contribue au remodelage, à l’inflammation et à la dysfonction endothéliale des artères pulmonaires.En conclusion, ce travail de thèse a permis de mettre en évidence des mécanismes contribuant à la surexpression du NGF dans l’HTP, et de confirmer sa participation à la progression de la maladie. L’ensemble des résultats obtenus renforce ainsi le NGF comme cible d’intérêt thérapeutique dans l’HTP
Pulmonary hypertension (PH) is a severe disease characterized by an increase in mean pulmonary arterial pressure over 20mmHg at rest, compared with 14mmHg in healthy individuals. Ultimately, PH leads to right heart failure and death. In the absence of any curative treatment, identification of new therapeutic targets is a major challenge. In this context, a better understanding of PH development and progression is crucial. In our laboratory, one target of interest is the nerve growth factor or NGF, overexpressed in pulmonary arteries both in experimental and human PH, and playing a significant role in three major PH features: pulmonary arterial inflammation, reactivity and remodeling.First, we focused on possible mechanisms activated in PH that may contribute to NGF pulmonary arterial increased expression. We showed that pro-inflammatory cytokines whose expression are increased in PH, such as interleukin-1β (IL-1β) or Tumor necrosis factor-α, as well as oxidative stress can increase NGF expression and secretion by pulmonary arterial endothelial cells - EC- or smooth muscle cells -CML-. We showed that this secretion involved Transforming growth factor β1, which is secreted by both ECs and SMCs, and then acts in an autocrine manner on these cells to stimulate NGF secretion.We then studied the role of NGF in two major PH features: pulmonary arterial hyperreactivity and inflammation.Regarding hyperreactivity first, we showed that a chronic treatment with NGF (24h) led to pulmonary arterial hyperreactivity, by enhancing activity of connexin-43-dependent gap junctions in SMCs. In parallel, we showed that a shorter treatment with NGF (1h) also led to led to pulmonary arterial hyperreactivity, but in a connexin-43-independent manner, with deregulation of intracellular calcium signaling and increased sensitization of the contractile apparatus in SMCs.Regarding the link between NGF and inflammation, our results showed that in vivo, in a rat model of PH, a preventive treatment with anti-NGF blocking antibodies reduced pulmonary arterial monocyte/macrophage infiltration and inflammasome protein expression as well as both circulating and pulmonary levels of IL-1β. In vitro, we showed that NGF is able to attract monocytes, and that IL-1β plays an important role in pulmonary arterial remodeling, inflammation and endothelial dysfunction.In conclusion, this work has highlighted mechanisms contributing to NGF increased expression in PH and confirmed its involvement in the progression of the disease. The overall results obtained further support NGF as a therapeutic target of interest in this disease