The Role of Type 2 Inflammation in Schistosoma-Induced Pulmonary Hypertension

Mickael, Claudia; Graham, Brian B.

doi:10.3389/fimmu.2019.00027

Cited by 19 publications

(17 citation statements)

References 32 publications

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“…Many studies have started to dissect the immunological events that underlie SchPH pathogenesis (1,61,87,89,92,96,97,(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114). The current understanding of the signaling events is summarized in Figure 6.…”

Section: Current Concepts Of Schpah Disease Pathogenesismentioning

confidence: 99%

“…Schistosoma-associated pulmonary arterial hypertension (SchPAH) is a fatal complication of chronic schistosomiasis infection, and a leading cause of PAH-related morbidity and mortality worldwide (1,2). The lack of understanding of pathogenic mechanisms contributes to the absence of effective therapy, resulting in worsening of the inflammatory condition and overall poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

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Schistosomiasis Pulmonary Arterial Hypertension

et al. 2020

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Pulmonary arterial hypertension (PAH) is a disease of the lung blood vessels that results in right heart failure. PAH is thought to occur in about 5% to 10% of patients with hepatosplenic schistosomiasis, particularly due to S. mansoni. The lung blood vessel injury may result from a combination of embolization of eggs through portocaval shunts into the lungs causing localized Type 2 inflammatory response and vessel remodeling, triggering of autonomous pathology that becomes independent of the antigen, and high cardiac output as seen in portopulmonary hypertension. The condition is likely underdiagnosed as there is little systematic screening, and risk factors for developing PAH are not known. Screening is done by echocardiography, and formal diagnosis requires invasive right heart catheterization. Patients with Schistosoma-associated PAH show reduced functional capacity and can be treated with pulmonary vasodilators, which improves symptoms and may improve survival. There are animal models of this disease that might help in understanding disease pathogenesis and identify novel targets to screen and treatment. Pathogenic mechanisms include Type 2 immunity and activation and signaling in the TGF-β pathway. There are still major uncertainties regarding Schistosoma-associated PAH development, course and treatment.

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Section: Current Concepts Of Schpah Disease Pathogenesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Schistosomiasis Pulmonary Arterial Hypertension

et al. 2020

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“…[26][27][28][29][30][31] More recently, type 2 immunity is thought to play a significant role in muscularization of the pulmonary vasculature. [32][33][34][35][36] Furthermore, despite advances in understanding some of the effects of pulmonary vascular remodeling to the development of emphysema, its effect on the phenotypic manifestations and severity of epithelial remodeling in CLD remain unknown. These gaps in knowledge underscore the need for future mechanistic investigations of the crosstalk between the vasculature and airways in CLD.…”

Section: Introductionmentioning

confidence: 99%

Optimization of combined measures of airway physiology and cardiovascular hemodynamics in mice

et al. 2020

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Pulmonary hypertension may arise as a complication of chronic lung disease typically associated with tissue hypoxia, as well as infectious agents or injury eliciting a type 2 immune response. The onset of pulmonary hypertension in this setting (classified as Group 3) often complicates treatment and worsens prognosis of chronic lung disease. Chronic lung diseases such as chronic obstructive lung disease (COPD), emphysema, and interstitial lung fibrosis impair airflow and alter lung elastance in addition to affecting pulmonary vascular hemodynamics that may culminate in right ventricle dysfunction. To date, functional endpoints in murine models of chronic lung disease have typically been limited to separately measuring airway and lung parenchyma physiology. These approaches may be lengthy and require a large number of animals per experiment. Here, we provide a detailed protocol for combined assessment of airway physiology with cardiovascular hemodynamics in mice. Ultimately, a comprehensive overview of pulmonary function in murine models of injury and disease will facilitate the integration of studies of the airway and vascular biology necessary to understand underlying pathophysiology of Group 3 pulmonary hypertension.

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“…[5], until painful and variable clinical conditions of the chronic and advanced disease. The parasite and/or its eggs can lodge outside the hepatic portal system, causing the ectopic [6], neurological [7], vasculopulmonary [8], and renal [9] forms of the disease. The cognitive and physical consequences of the schistosomiasis implicate directly on the morbidity, being responsible for an annual loss of 4.5 million disability-adjusted life years (DALYs) [10].…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni

et al. 2020

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Schistosomiasis is a serious public health problem, prevalent in tropical and subtropical areas, especially in poor communities without access to safe drinking water and adequate sanitation. Transmission has been reported in 78 countries, and its control depends on a single drug, praziquantel, which has been used over the past 30 years. Our work is focused on exploiting target‐based drug discovery strategies to develop new therapeutics to treat schistosomiasis. In particular, we are interested in evaluating the enzyme dihydroorotate dehydrogenase (DHODH) as a drug target. DHODH is a flavoenzyme that catalyzes the stereospecific oxidation of (S)‐dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. Previously, we identified atovaquone, used in the treatment of malaria, and its analogues, as potent and selective inhibitors against Schistosoma mansoni DHODH (SmDHODH). In the present article, we report the first crystal structure of SmDHODH in complex with the atovaquone analogue inhibitor 2‐((4‐fluorophenyl)amino)‐3‐hydroxynaphthalene‐1,4‐dione (QLA). We discuss three major findings: (a) the open conformation of the active site loop and the unveiling of a novel transient druggable pocket for class 2 DHODHs; (b) the presence of a protuberant domain, only present in Schistosoma spp DHODHs, that was found to control and modulate the dynamics of the inhibitor binding site; (c) a detailed description of an unexpected binding mode for the atovaquone analogue to SmDHODH. Our findings contribute to the understanding of the catalytic mechanism performed by class 2 DHODHs and provide the molecular basis for structure‐guided design of SmDHODH inhibitors. Database The structural data are available in Protein Data Bank (PDB) database under the accession code number https://www.rcsb.org/structure/6UY4.

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The Role of Type 2 Inflammation in Schistosoma-Induced Pulmonary Hypertension

Cited by 19 publications

References 32 publications

Schistosomiasis Pulmonary Arterial Hypertension

Schistosomiasis Pulmonary Arterial Hypertension

Optimization of combined measures of airway physiology and cardiovascular hemodynamics in mice

Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni

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