Intrapulmonary T Cells Are Sufficient for Schistosoma-Induced Pulmonary Hypertension.

BACKGROUND: Schistosomiasis is a parasitic infection that can cause pulmonary hypertension (PH). Th2 CD4 T cells are necessary for experimental Schistosoma-PH. However, if T cells migrate to the lung to initiate, the localized inflammation that drives vascular remodeling and PH is unknown. METHODS: Mice were sensitized to Schistosoma mansoni eggs intraperitoneally and then challenged using tail vein injection. FTY720 was administered, which blocks lymphocyte egress from lymph nodes. T cells were quantified using flow cytometry, PH severity via heart catheterization, and cytokine concentration through ELISA. RESULTS: FTY720 decreased T cells in the peripheral blood, and increased T cells in the mediastinal lymph nodes. However, FTY720 treatment resulted in no change in PH or type 2 inflammation severity in mice sensitized and challenged with S. mansoni eggs, and the number of memory and effector CD4 T cells in the lung parenchyma was also unchanged. Notably, intraperitoneal Schistosoma egg sensitization alone resulted in a significant increase in intravascular lymphocytes and T cells, including memory T cells, although there was no significant change in parenchymal cell density, IL-4 or IL-13 expression, or PH. CONCLUSION: Blocking T cell migration did not suppress PH following Schistosoma egg challenge. Memory CD4 T cells, located in the lung intravascular space following egg sensitization, appear sufficient to cause type 2 inflammation and PH.

Identification of Biomarkers for Schistosoma-Associated Pulmonary Arterial Hypertension Based on RNA-Seq Data of Mouse Whole Lung Tissues.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a deadly disease, and the molecular mechanism of PAH has not been clarified clearly. The objective of this study was to identify possible biomarkers and explore the potential mechanisms of Schistosoma-induced PAH. METHODS: GSE49114 RNA-Seq data developed from mouse whole lung tissues were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between control samples and schistosomiasis-induced PAH samples were identified by the edgeR software. Gene Ontology (GO) and pathway enrichment analysis of DEGs were performed, followed by metabolic pathway network construction. Moreover, pathways with higher connectivity degrees in the metabolic pathway network were identified. RESULTS: Totally, 877 up- and 520 downregulated DEGs were screened. The upregulated DEGs such as IL-4 (Interleukin-4) were significantly related with immune system process, transmembrane signaling receptor activity, and signal transducer activity. Downregulated DEGs (i.e., Smad9 (SMAD family member 9), BMPR2 (bone morphogenetic protein type 2 receptor), and Eng (endoglin)) were significantly enriched in signal transducer activity, growth factor binding, and signal transduction. The top 10 metabolic pathways with highest connectivity degree were screened, including leishmaniasis (degree = 26), antigen processing and presentation (degree = 20), hematopoietic cell lineage (degree = 20), chemokine signaling pathway (degree = 18), and JAK-STAT signaling pathway (degree = 18). CONCLUSIONS: Smad9, BMPR2, Eng and IL4, and their relative functions such as signal transduction, signal transducer activity, and immune system process might play important roles in schistosomiasis-induced PAH. Moreover, the interaction of metabolic pathways was critical in the development of schistosomiasis-PAH.

[Schistosomiasis and pulmonary hypertension]. / Sistosomiyazis ve pulmoner hipertansiyon.

Schistosomiasis is one of the most prevelant parazitic diseases in the world. It is endemic in more than 70 countries, and more than 200 million people worldwide are infected with Schistosoma. Pulmonary hypertension (PHT) is one of the chronic complications of schistosomiasis. The exact pathogenesis of schistosomiasis-associated pulmonary hypertension (S-PHT) remains unclear, although several mechanisms such as parazitic arterial embolisation, pulmonary arteriopathy, and portopulmonary hypertension have been suggested. Pathological pulmonary vascular changes in S-PHT were found similar to those in idiopathic pulmonary arterial hypertension (IPAH). The fact that schistosomiasis is one of the most common causes of pulmonary arterial hypertension (PAH), particularly in the developing countries, underlines the importance of enhancing our knowledge on this disease. Developments in the treatment of PAH have resulted in improved prognosis and significant increase in life expectancy and quality of life in the last two decades, which has enhanced the importance of S-PHT. Schistosomiasis is treated with praziquantel. Nevertheless, there is limited evidence that this treatment is effective for PHT. Although antihelmintic medications do not lead to significant improvement, they have beneficial effects and may slow down disease progression. Using PAH-specific treatments in the patients with schistosomiasis-associated PAH (S-PAH) can improve prognosis. However, inadequate clinical studies and limited sources in the endemic regions restrict extensive usage of these expensive medications. Further studies are required to determine the efficacy of these treatment modalities.

Hepatic Shunting of Eggs and Pulmonary Vascular Remodeling in Bmpr2(+/-) Mice with Schistosomiasis.

RATIONALE: Schistosomiasis is a major cause of pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein type-II receptor (BMPR-II) are the commonest genetic cause of PAH. OBJECTIVES: To determine whether Bmpr2(+/-) mice are more susceptible to schistosomiasis-induced pulmonary vascular remodeling. METHODS: Wild-type (WT) and Bmpr2(+/-) mice were infected percutaneously with Schistosoma mansoni. At 17 weeks postinfection, right ventricular systolic pressure and liver and lung egg counts were measured. Serum, lung and liver cytokine, pulmonary vascular remodeling, and liver histology were assessed. MEASUREMENTS AND MAIN RESULTS: By 17 weeks postinfection, there was a significant increase in pulmonary vascular remodeling in infected mice. This was greater in Bmpr2(+/-) mice and was associated with an increase in egg deposition and cytokine expression, which induced pulmonary arterial smooth muscle cell proliferation, in the lungs of these mice. Interestingly, Bmpr2(+/-) mice demonstrated dilatation of the hepatic central vein at baseline and postinfection, compared with WT. Bmpr2(+/-) mice also showed significant dilatation of the liver sinusoids and an increase in inflammatory cells surrounding the central hepatic vein, compared with WT. This is consistent with an increase in the transhepatic passage of eggs. CONCLUSIONS: This study has shown that levels of BMPR-II expression modify the pulmonary vascular response to chronic schistosomiasis. The likely mechanism involves the increased passage of eggs to the lungs, caused by altered diameter of the hepatic veins and sinusoids in Bmpr2(+/-) mice. Genetically determined differences in the remodeling of hepatic vessels may represent a new risk factor for PAH associated with schistosomiasis.

Transforming growth factor-ß signaling promotes pulmonary hypertension caused by Schistosoma mansoni.

BACKGROUND: The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor-ß (TGF-ß) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease. METHODS AND RESULTS: Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase-dependent vasoconstriction accounted for ≈60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF-ß signaling, as pharmacological blockade of the TGF-ß ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF-ß signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF-ß signaling in their remodeled pulmonary arteries. CONCLUSION: Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF-ß signaling.

Interstitial macrophage phenotypes in Schistosoma-induced pulmonary hypertension.

Background: Schistosomiasis is a common cause of pulmonary hypertension (PH) worldwide. Type 2 inflammation contributes to the development of Schistosoma-induced PH. Specifically, interstitial macrophages (IMs) derived from monocytes play a pivotal role by producing thrombospondin-1 (TSP-1), which in turn activates TGF-ß, thereby driving the pathology of PH. Resident and recruited IM subpopulations have recently been identified. We hypothesized that in Schistosoma-PH, one IM subpopulation expresses monocyte recruitment factors, whereas recruited monocytes become a separate IM subpopulation that expresses TSP-1. Methods: Mice were intraperitoneally sensitized and then intravenously challenged with S. mansoni eggs. Flow cytometry on lungs and blood was performed on wildtype and reporter mice to identify IM subpopulations and protein expression. Single-cell RNA sequencing (scRNAseq) was performed on flow-sorted IMs from unexposed and at day 1, 3 and 7 following Schistosoma exposure to complement flow cytometry based IM characterization and identify gene expression. Results: Flow cytometry and scRNAseq both identified 3 IM subpopulations, characterized by CCR2, MHCII, and FOLR2 expression. Following Schistosoma exposure, the CCR2+ IM subpopulation expanded, suggestive of circulating monocyte recruitment. Schistosoma exposure caused increased monocyte-recruitment ligand CCL2 expression in the resident FOLR2+ IM subpopulation. In contrast, the vascular pathology-driving protein TSP-1 was greatest in the CCR2+ IM subpopulation. Conclusion: Schistosoma-induced PH involves crosstalk between IM subpopulations, with increased expression of monocyte recruitment ligands by resident FOLR2+ IMs, and the recruitment of CCR2+ IMs which express TSP-1 that activates TGF-ß and causes PH.

Praziquantel reverses pulmonary hypertension and vascular remodeling in murine schistosomiasis.

RATIONALE: Schistosomiasis is the most common worldwide cause of pulmonary arterial hypertension. The anti-schistosome drug praziquantel has been shown to reverse the liver fibrosis associated with Schistosoma mansoni in mice. OBJECTIVES: We sought to determine whether praziquantel reverses established pulmonary vascular remodeling and pulmonary hypertension in a mouse model of S. mansoni. METHODS: Mice were infected percutaneously with S. mansoni. At 17 weeks after infection mice were either killed or received two doses of praziquantel or vehicle by oral gavage. Treated mice were studied at 25 weeks after infection. MEASUREMENTS AND MAIN RESULTS: Vehicle-treated mice demonstrated significant increases in right ventricular systolic pressures (RVSP) and right ventricular hypertrophy (RVH) at 25 weeks, accompanied by pulmonary vascular remodeling. The degree of vascular remodeling correlated with proximity to granulomas. The elevation of RVSP and RVH at 25 weeks was dependent on the presence of eggs in the lung. Praziquantel eliminated the production of eggs in feces and led to clearance of eggs from the lung and to a lesser extent from liver. Praziquantel prevented the rise in RVSP and RVH seen in vehicle-treated mice and reversed established pulmonary vascular remodeling. Praziquantel significantly reduced lung mRNA expression of IL-13, IL-8, and IL-4, but did not reduce serum cytokine levels. CONCLUSIONS: The development of pulmonary hypertension associated with S. mansoni infection can be prevented by praziquantel, and established vascular remodeling can be reversed. The mechanism involves clearance of lung eggs and reduced local expression of lung cytokines.

Cardiopulmonary manifestations of hepatosplenic schistosomiasis.

BACKGROUND: Schistosomiasis is a highly prevalent disease with >200 million infected people. Pulmonary hypertension is one of the pulmonary manifestations in this disease, particularly in its hepatosplenic presentation. The aim of this study was to determine the prevalence of pulmonary hypertension in schistosomiasis patients with the hepatosplenic form of the disease. METHODS AND RESULTS: All patients with hepatosplenic schistosomiasis followed up at the gastroenterology department of our university hospital underwent echocardiographic evaluation to search for pulmonary hypertension. Patients presenting with systolic pulmonary artery pressure >40 mm Hg were further evaluated through right heart catheterization. Our study showed an 18.5% prevalence of patients with elevated systolic pulmonary artery pressure at echocardiography. Invasive hemodynamics confirmed the presence of pulmonary hypertension in 7.7% (95% confidence interval, 3.3 to 16.7) of patients, with a prevalence of precapillary (arterial) pulmonary hypertension of 4.6% (95% confidence interval, 1.5 to 12.7). CONCLUSIONS: Our study reinforces the role of echocardiography as a screening tool in the investigation of pulmonary hypertension, together with the need for invasive monitoring for a proper diagnosis. We conclude that hepatosplenic schistosomiasis may account for one of the most prevalent forms of pulmonary hypertension worldwide, justifying the development of further studies to evaluate the effect of specific pulmonary hypertension treatment in this particular form of the disease.

Pulmonary artery thrombosis in experimental Angiostrongylus vasorum infection does not result in pulmonary hypertension and echocardiographic right ventricular changes.

BACKGROUND: Dogs experimentally inoculated with Angiostrongylus vasorum develop severe pulmonary parenchymal lesions and arterial thrombosis at the time of patency. HYPOTHESIS: A. vasorum-induced thrombosis results in arterial hypoxemia, pulmonary hypertension (PH), and altered cardiac morphology and function. ANIMALS: Six healthy Beagles experimentally inoculated with A. vasorum. METHODS: Thoracic radiographs and arterial blood gas analyses were performed 8 and 13 weeks postinoculation (wpi) and 9 weeks posttherapy (wpt). Echocardiography was done before and 2, 5, 8, 13 wpi and 9 wpt. Invasive pulmonary artery pressure (PAP) measurements were obtained 8 wpi. Two untreated dogs were necropsied 13 wpi and 4 treated dogs 9 wpt. RESULTS: All dogs had patent infections at 7 wpi and clinical respiratory signs at 8 wpi. Moderate hypoxemia (median PaO2 of 73 and 74 mmHg) present at 8 and 13 wpi had resolved by 9 wpt. Echocardiographically, no evidence of PH and no abnormalities in cardiac size and function were discernible at any time point. PAP invasively measured at 8 wpi was not different from that of control dogs. Severe radiographic pulmonary parenchymal and suspected thrombotic lesions at 13 wpi were corroborated by necropsy. Most histopathologic changes had resolved at 9 wpt, but focal inflammatory, thrombotic, and fibrotic changes still were present in all dogs. CONCLUSION: In experimentally infected Beagles, pulmonary and vascular changes induced by A. vasorum are reflected by marked radiographic changes and arterial hypoxemia. These did not result in PH and echocardiographic changes in cardiac size and function.

Schistosomiasis associated pulmonary hypertension.

Schistosomiasis is one of the most prevalent infectious diseases, endemic in more than 70 countries, mainly within the developing world. More than 200 million people might be infected worldwide; about 20 million of those might develop severe disease. The hepatosplenic form of schistosomiasis is the most prevalent form of chronic disease, characterised by the presence of periportal fibrosis and portal hypertension. Pulmonary hypertension is a well-recognised complication of hepatosplenic schistosomiasis. Recent prevalent studies revealed that schistosomiasis patients may develop precapillary and postcapillary forms of pulmonary hypertension, reinforcing the role of invasive haemodynamic measurements for the proper diagnosis. These studies also demonstrated that schistosomiasis associated pulmonary arterial hypertension may represent the most prevalent form of pulmonary arterial hypertension (PAH). Many aspects regarding the appropriate management of Sch-PAH patients still remain to be elucidated, as the use of specific PAH therapy. Although the ongoing control programmes that started within the 1980s have clearly improved the schistosomiasis cenario worldwide, Sch-PAH will be seen for decades after proper control is reached, strengthening the current need for comprehensive studies aiming to clarify the multiple mechanisms involved in the pathophysiology of this particular subgroup of PAH.

Unusual location of hydatid cyst: the posterior leaflet of tricuspid valve.

Hydatid Cyst disease involves the heart in 0.02-2% of the cases. It can appear with symptoms very similar to coronary artery disease, cardiac valvular disease and pericarditis. We present a case of hydatid cyst that was located on the posterior tricuspid leaflet and that caused tricuspid regurgitation in 37 year old female patient who has gone through hydatid cyst excision from the bilateral lungs with median sternotomy 2 years ago. In addition to the right atrial and ventricular dilatation, second degree tricuspid regurgitation and significant pulmonary hypertension was found. The 2 x 2 cm smooth surfaced mass was resected from the posterior leaflet of the tricuspid valve and the defect was closed with suture with the aid of cardiopulmonary bypass. The patient followed with long term albendazole treatment. Cardiac echinococcosis should be kept in mind in some patients throughout their life with a history of previous hydatid cyst disease. Surgical excision without rupture is the treatment of choice for cardiac hydatid cyst, with following medical therapy in order to prevent recurrence.

Pulmonary arterial response to Angiostrongylus vasorum in naturally infected dogs: echocardiographic findings in two cases.

BACKGROUND: Angiostrongylus vasorum is a nematode living in the pulmonary arteries of canids. Infected dogs develop severe pulmonary lesions which can potentially lead to pulmonary hypertension (PH). However, reports of PH in natural infected dogs are scant. One of the possible causes of the low prevalence of PH in A. vasorum-infected dogs could be the establishment of large diameter intrapulmonary arteriovenous anastomoses (IPAVAs), which attenuate pulmonary vascular resistance, thus reducing the pulmonary arterial pressure. The present report describes the pulmonary arterial pressure (PAP) response to A. vasorum natural infection in two dogs, assessed by echocardiography and by the saline contrast echocardiographic test (SCE). RESULTS: Both dogs showed clinical signs of respiratory disease. At presentation, case 1 did not show echocardiographic signs of PH and the SCE test was positive proving the presence of IPAVAs. However, at the follow-up visit, despite A. vasorum infection resolution, the same dog showed PH and the SCE test resulted negative, which ruled out the presence of IPAVAs. Case 2 suffered from severe pulmonary arterial hypertension and right-side congestive heart failure since the day of presentation. Saline contrast echocardiography was negative both at the time of presentation and at the follow-up visit. CONCLUSIONS: In the two cases described above, the PH was not associated with IPAVAs. During A. vasorum infection, IPAVAs recruitment mechanism is able to contrast the rise of PAP until a certain level. It probably represents an initial escape mechanism of PH that, over time, exhausts its compensatory capacities allowing PAP to rise and to be detectable on echocardiography.

Th2 CD4+ T Cells Are Necessary and Sufficient for Schistosoma-Pulmonary Hypertension.

Background Inflammation underlies many forms of pulmonary hypertension (PH), including that resulting from Schistosoma infection, a major cause of PH worldwide. Schistosomiasis-associated PH is proximately triggered by embolization of parasite eggs into the lungs, resulting in localized type 2 inflammation. However, the role of CD4+ T cells in this disease is not well defined. Methods and Results We used a mouse model of schistosomiasis-associated PH, induced by intraperitoneal egg sensitization followed by intravenous egg challenge, with outcomes including right ventricle systolic pressure measured by cardiac catheterization, and cell density and phenotype assessed by flow cytometry. We identified that embolization of Schistosoma eggs into lungs of egg-sensitized mice increased the perivascular density of T-helper 2 (Th2) CD4+ T cells by recruitment of cells from the circulation and triggered type 2 inflammation. Parabiosis confirmed that egg embolization is required for localized type 2 immunity. We found Th2 CD4+ T cells were necessary for Schistosoma-induced PH, given that deletion of CD4+ T cells or inhibiting their Th2 function protected against type 2 inflammation and PH following Schistosoma exposure. We also observed that adoptive transfer of Schistosoma-sensitized CD4+ Th2 cells was sufficient to drive type 2 inflammation and PH. Conclusions Th2 CD4+ T cells are a necessary and sufficient component for the type 2 inflammation-induced PH following Schistosoma exposure.

[Etiological diagnosis of pulmonary hypertension: A cause of difficult diagnosis]. / Diagnostic étiologique de l'hypertension pulmonaire : une cause de diagnostic difficile.

INTRODUCTION: Schistosomiasis associated pulmonary arterial hypertension belongs to group 1 of the pulmonary hypertension classification and should be considered in any patient with pulmonary hypertension returning from an endemic area. CASE REPORT: A 17-year-old patient was hospitalized for pulmonary hypertension detected during the initial assessment of viral hepatitis B-related cirrhosis with portal hypertension. The initial assessment established the diagnosis of pulmonary hypertension secondary to viral hepatitis B-cirrhosis. The patient's hepatic and haemodynamic condition deteriorated and he was treated with intravenous epoprostenol. This allowed subsequent performance of a liver transplantation. Epoprostenol could then be discontinued. Unexpectedly, histology of the liver explant revealed florid schistosomiasis in addition to hepatitis B cirrhosis. CONCLUSION: The diagnosis of pulmonary arterial hypertension associated with schistosomiasis may be difficult. It is necessary to repeat the serological studies and, sometimes, to obtain a rectal biopsy. The treatment of pulmonary arterial hypertension associated with schistosomiasis is based on specific therapies and antiparasitic treatment.

Aberrant migration and surgical removal of a heartworm (Dirofilaria immitis) from the femoral artery of a cat.

A cat was evaluated for an acute-onset of right pelvic limb paresis. Thoracic radiographs revealed normal cardiac size and tortuous pulmonary arteries. Abdominal ultrasound identified a heartworm (HW) extending from the caudal abdominal aorta into the right external iliac artery and right femoral artery. The cat was HW-antigen positive. Echocardiography revealed a HW within the right branch of the main pulmonary artery and evidence of pulmonary hypertension. An agitated-saline contrast echocardiogram revealed a small right to left intracardiac shunt at the level of the atria. Surgical removal of the HW was performed with no substantial postoperative complications. There was return of blood flow and improved motor function to the limb. The cat remains mildly paretic on the affected limb with no other clinical signs.

Cardiac manifestations of parasitic infections part 3: pericardial and miscellaneous cardiopulmonary manifestations.

This is part three of a three-part series discussing parasites of the heart. In this section, we present an overview on parasitic diseases involving predominantly the pericardium and other miscellaneous cardiopulmonary manifestations such as some pulmonary hypertension syndromes and endomyocardial fibrosis.

Acute phase proteins and markers of oxidative stress to assess the severity of the pulmonary hypertension in heartworm-infected dogs.

BACKGROUND: Canine heartworm infection is characterized by pulmonary endarteritis and pulmonary hypertension (PH). The aim of the present study was to evaluate the relationship between PH with the concentrations of different positive (C-reactive protein [CRP] and haptoglobin [Hp]) and negative (albumin and paraoxonase-1 [PON-1]) acute phase proteins (APP), as well as the oxidative stress, by measuring glutathione peroxidase (GPx) and total antioxidant capacity (TAC) in 27 heartworm-infected dogs on Day 0 (diagnosis) and Day 120 (1 month after the last adulticide injection). Presence/absence of PH was determined by the Right Pulmonary Artery Distensibility (RPAD) Index. RESULTS: On Day 0, 62.9% of the dogs showed PH. Concentrations of CRP and Hp were higher in dogs with PH, especially in dogs with moderate-severe PH (P < 0.005 and P < 0.05, respectively). Albumin and PON-1 concentrations were higher in dogs without PH (P < 0.05 for albumin). On Day 120, 59.2% of the dogs presented with PH; CRP decreased while Hp increased (P < 0.005 and P < 0.05, respectively). Also, albumin and PON-1 rose, especially in absence of PH. There were not significant changes in the serum values of GPx and TAC. CONCLUSIONS: CRP and Hp have a potential prognostic role in dogs with dirofilariasis because increases in positive APP correlated with presence and severity of PH. CRP decreased, but Hp persisted at an elevated level in dogs with PH 1 month after the end of the adulticide treatment. CRP and Hp could work as early biomarkers of PH and be useful to stage the disease and to monitor the evolution of the patient and indirectly evaluate the persistence of arterial damage after the parasites have been eliminated. Albumin and PON-1 also showed potential value as markers of PH, although further research is necessary to determine its utility.