Aims: Transforming growth factor-β (TGF-β) signalling is required for chronic hypoxia-induced pulmonary hypertension (PH). The activation of TGF-β by thrombospondin-1 (TSP-1) contributes to the pathogenesis of hypoxia-induced PH. However, neither the cellular source of pathologic TSP-1 nor the downstream signalling pathway that link activated TGF-β to PH have been determined. In this study, we hypothesized that circulating monocytes, which are recruited to become interstitial macrophages (IMs), are the major source of TSP-1 in hypoxia-exposed mice, and TSP-1 activates TGF-β with increased Rho-kinase signalling, causing vasoconstriction. Methods and results: Flow cytometry revealed that a specific subset of IMs is the major source of pathologic TSP-1 in hypoxia. Intravenous depletion and parabiosis experiments demonstrated that these cells are circulating prior to recruitment into the interstitium. Rho-kinase-mediated vasoconstriction was a major downstream target of active TGF-β. Thbs1 deficient bone marrow (BM) protected against hypoxic-PH by blocking TGF-β activation and Rho-kinase-mediated vasoconstriction. Conclusion: In hypoxia-challenged mice, BM derived and circulating monocytes are recruited to become IMs which express TSP-1, resulting in TGF-β activation and Rho-kinase-mediated vasoconstriction.

Hypoxia is a major cause of pulmonary hypertension (PH) worldwide, and it is likely that interstitial pulmonary macrophages contribute to this vascular pathology. We observed in hypoxia-exposed mice an increase in resident interstitial macrophages, which expanded through proliferation and expressed the monocyte recruitment ligand CCL2. We also observed an increase in CCR2 ⁺ macrophages through recruitment, which express the protein thrombospondin-1, which functionally activates TGF-β to cause vascular disease. Blockade of monocyte recruitment with either CCL2-neutralizing antibody treatment or CCR2 deficiency in the bone marrow compartment suppressed hypoxic PH. These data were supported by analysis of plasma samples from humans who traveled from low (225 m) to high (3500 m) elevation, revealing an increase in thrombospondin-1 and TGF-β expression following ascent, which was blocked by dexamethasone prophylaxis. In the hypoxic mouse model, dexamethasone prophylaxis recapitulated these findings by mechanistically suppressing CCL2 expression and CCR2 ⁺ monocyte recruitment. These data suggest a pathologic cross talk between 2 discrete interstitial macrophage populations, which can be therapeutically targeted.

Schistosomiasis-induced pulmonary hypertension (PH) is a significant global health burden, yet the underlying mechanisms remain poorly understood. We demonstrate that Schistosoma exposure leads to platelet accumulation in the lung and platelet activation. We observed increased plasma levels of C3a and C5a, indicative of complement system activation, and elevated expression of platelet complement proteins and receptors. These findings underscore the role of platelets and complement in the inflammatory responses associated with Schistosoma-induced PH.

Background: Schistosomiasis is a major cause of pulmonary hypertension (PH) worldwide, and CD4 T cells are critical in disease pathogenesis. The role of dendritic cells (DCs) in Schistosoma-induced PH (SchPH) is unknown. There are two types of conventional DCs, cDC1 and cDC2, that prototypically activate CD8 and CD4 T cells, respectively. Methods: We exposed wildtype, DC reporter, and DC knockout mice to Schistosoma mansoni and quantified PH severity by heart catheterization and cell density by flow cytometry. Results: Experimental S. mansoni exposure increased the density of pulmonary DCs, particularly cDC2s. Deleting both cDC subsets did not significantly modify SchPH disease severity. Deleting only cDC1s caused more severe SchPH, associated with more Th2 CD4 and CD8 T cells. In contrast, deleting only cDC2s reduced SchPH disease severity. Conclusions: cDC1s appear to be protective, whereas cDC2s promote disease in SchPH.

Background: Schistosomiasis, a major cause of pulmonary arterial hypertension (PAH) worldwide, is most clearly described complicating infection by one species,Schistosoma mansoni. Controlled exposure of mice can be used to induce Type 2 inflammation-dependentS.mansonipulmonary hypertension (PH). We sought to determine if another common species,S.japonicum, can also cause experimental PH.Methods: Schistosome eggs were obtained from infected mice, and administered by intraperitoneal sensitization followed by intravenous challenge to experimental mice, which underwent right heart catheterization and tissue analysis.Results: S.japonicumsensitized and challenged mice developed PH, which was milder than that followingS.mansonisensitization and challenge. The degree of pulmonary vascular remodeling and Type 2 inflammation in the lungs was similarly proportionate. Cross-sensitization revealed that antigens from either species are sufficient to sensitize for intravenous challenge with either egg, and the degree of PH severity depended on primarily the species used for intravenous challenge. Compared to a relatively uniform distribution ofS.mansonieggs,S.japonicumeggs were observed in clusters in the lungs.Conclusions: S.japonicumcan induce experimental PH, which is milder than that resulting from comparableS.mansoniexposure. This difference may result from the distribution of eggs in the lungs, and is independent of which species is used for sensitization. This result is consistent with the clearer association betweenS.mansoniinfection and the development of schistosomiasis-associated PAH in humans.