Inflammation, immunological reaction and role of infection in pulmonary hypertension

Pullamsetti, Soni Savai; Savai, Rajkumar; Janssen, Wiebke; Dahal, Bhola K.; Seeger, Werner; Grimminger, Friedrich; Ghofrani, Hossein Ardeschir; Weißmann, Norbert; Schermuly, Ralph Theo

doi:10.1111/j.1469-0691.2010.03285.x

Cited by 80 publications

(63 citation statements)

References 54 publications

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“…One key risk factor that has a prominent role in the initiation and/or development of pulmonary hypertension is inflammation. 21 Inflammation can be triggered by chronic alveolar hypoxia, 5 as well as infection, 7 vascular injury due to aberrant blood flow, 15 toxins, 12 and autoimmune conditions. 20 Swainsonine contained in locoweed (genera Astragalus and Oxytropis) is a mediator of pulmonary hypertension in calves 13 but was not observed to be a risk factor during the present study.…”

Section: Discussionmentioning

confidence: 99%

An investigation into beef calf mortality on five high-altitude ranches that selected sires with low pulmonary arterial pressures for over 20 years

et al. 2013

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Producer reports from ranches over 2,438 meters in southwest Colorado suggest that the mortality of preweaned beef calves may be substantially higher than the national average despite the selection of low pulmonary pressure herd sires for over 20 years. Diagnostic investigations of this death loss problem have been limited due to the extensive mountainous terrain over which these calves are grazed with their dams. The objective of the current study was to determine the causes of calf mortality on 5 high-altitude ranches in Colorado that have been selectively breeding sires with low pulmonary pressure (<45 mmHg) for over 20 years. Calves were followed from branding (6 weeks of age) in the spring to weaning in the fall (7 months of age). Clinical signs were recorded, and blood samples were taken from sick calves. Postmortem examinations were performed, and select tissue samples were submitted for aerobic culture and/or histopathology. On the principal study ranch, 9.6% (59/612) of the calves that were branded in the spring either died or were presumed dead by weaning in the fall. In total, 28 necropsies were performed: 14 calves (50%) had lesions consistent with pulmonary hypertension and right-sided heart failure, and 14 calves (50%) died from bronchopneumonia. Remodeling of the pulmonary arterial system, indicative of pulmonary hypertension, was evident in the former and to varying degrees in the latter. There is a need to better characterize the additional risk factors that complicate pulmonary arterial pressure testing of herd sires as a strategy to control pulmonary hypertension.

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Section: Discussionmentioning

confidence: 99%

An investigation into beef calf mortality on five high-altitude ranches that selected sires with low pulmonary arterial pressures for over 20 years

et al. 2013

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“…Several studies have shown increased muscularization of pulmonary arterial walls and collagen accumulation within pulmonary arteries in pulmonary hypertension (36,44). A role for inflammatory cytokines in this process has been suggested (28,35). To investigate possible mechanisms involved in the reduced pulmonary hypertension in ASC Ϫ/Ϫ mice, muscularization of peripheral pulmonary arteries was assessed in WT, ASC Ϫ/Ϫ , and NLRP3 Ϫ/Ϫ mice exposed to chronic hypoxia.…”

Section: Reduced Muscularization Of Arteries and Collagen Deposition mentioning

confidence: 99%

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Cero

Hillestad

Sjaastad

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary hypertension is a serious condition that can lead to premature death. The mechanisms involved are incompletely understood although a role for the immune system has been suggested. Inflammasomes are part of the innate immune system and consist of the effector caspase-1 and a receptor, where nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) is the best characterized and interacts with the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). To investigate whether ASC and NLRP3 inflammasome components are involved in hypoxiainduced pulmonary hypertension, we utilized mice deficient in ASC and NLRP3. Active caspase-1, IL-18, and IL-1␤, which are regulated by inflammasomes, were measured in lung homogenates in wild-type (WT), ASC Ϫ/Ϫ , and NLRP3 Ϫ/Ϫ mice, and phenotypical changes related to pulmonary hypertension and right ventricular remodeling were characterized after hypoxic exposure. Right ventricular systolic pressure (RVSP) of ASC Ϫ/Ϫ mice was significantly lower than in WT exposed to hypoxia (40.8 Ϯ 1.5 mmHg vs. 55.8 Ϯ 2.4 mmHg, P Ͻ 0.001), indicating a substantially reduced pulmonary hypertension in mice lacking ASC. Magnetic resonance imaging further supported these findings by demonstrating reduced right ventricular remodeling. RVSP of NLRP3Ϫ/Ϫ mice exposed to hypoxia was not significantly altered compared with WT hypoxia. Whereas hypoxia increased protein levels of caspase-1, IL-18, and IL-1␤ in WT and NLRP3 Ϫ/Ϫ mice, this response was absent in ASC Ϫ/Ϫ mice. Moreover, ASC Ϫ/Ϫ mice displayed reduced muscularization and collagen deposition around arteries. In conclusion, hypoxia-induced elevated right ventricular pressure and remodeling were attenuated in mice lacking the inflammasome adaptor protein ASC, suggesting that inflammasomes play an important role in the pathogenesis of pulmonary hypertension.inflammation; innate immunity; pulmonary vasculature PULMONARY HYPERTENSION can be a life-threatening condition leading to right-sided heart failure and premature death (5, 40). The pathogenesis of the various forms of pulmonary hypertension is not fully known, and insight into disease mechanisms is important for the development of improved treatment options for this severe condition. The role and importance of inflammation and immune activation in the development of pulmonary hypertension are not fully understood; however, inflammation has emerged as an important player. Clinically, increased circulating levels of IL-1␤ and IL-18 have been observed in patients with pulmonary arterial hypertension, indicating that inflammasomes can be activated in this condition (18,41). It is well known that innate immunity is activated in response to infection. However, in the last decade, new knowledge has emerged demonstrating that inflammatory pathways can also be activated as a result of cellular stress during sterile inflammation and that these inflammatory responses involve activation of inflammasomes (27). Inflammasome...

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“…2,3 Evidence for active, maladaptive infl ammatory processes is manifest in both humans with PH and animal models of the disease. 4 The scientifi c basis for infl ammation in PH has recently been summarized 5 and implicates innate and adaptive immune cells, mediators and effectors of infl ammation, and potential triggering events. Of particular interest to us is the collection of data implicating T and B cells in the pathobiologic aspects of PH and their interactions with mononuclear phagocytic cells.…”

Section: Original Research Pulmonary Vascular Diseasementioning

confidence: 99%

Circulating Myeloid-Derived Suppressor Cells Are Increased and Activated in Pulmonary Hypertension

Yeager

Nguyen

Belchenko

et al. 2012

Chest

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Pulmonary hypertension (PH) is a progressive syndrome with a poor prognosis that results in right-sided heart failure. 1 Although heterogeneous in its pathobiologic characteristics, it is distinguished in children and adults by cellular and structural changes in the full thickness of the walls of pulmonary arteries and by perivascular accumulation of infl ammatory cells. 2,3 Evidence for active, maladaptive infl ammatory processes is manifest in both humans with PH and animal models of the disease. 4 The scientifi c basis for infl ammation in PH has recently been summarized 5 and implicates innate and adaptive immune cells, mediators and effectors of infl ammation, and potential triggering events. Of particular interest to us is the collection of data implicating T and B cells in the pathobiologic aspects of PH and their interactions with mononuclear phagocytic cells. It has been suggested that a subpopulation of monocyte-derived dendritic cells (DCs) is functionally impaired in idiopathic PH 6 and that the presence of immature DCs may alter the T and B cell responses in the hypertensive lung. 7 Myeloid-derived suppressor cells (MDSCs) compose a phenotypically diverse subpopulation of cells

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Inflammation, immunological reaction and role of infection in pulmonary hypertension

Cited by 80 publications

References 54 publications

An investigation into beef calf mortality on five high-altitude ranches that selected sires with low pulmonary arterial pressures for over 20 years

An investigation into beef calf mortality on five high-altitude ranches that selected sires with low pulmonary arterial pressures for over 20 years

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice

Circulating Myeloid-Derived Suppressor Cells Are Increased and Activated in Pulmonary Hypertension

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