Endothelial-Specific Loss of Sphingosine-1-Phosphate Receptor 1 Increases Vascular Permeability and Exacerbates Bleomycin-induced Pulmonary Fibrosis

Knipe, Rachel S.; Spinney, Jillian J; Abe, Elizabeth A; Probst, Clemens K.; Franklin, A; Logue, Amanda; Giacona, F.; Drummond, Matt; Griffith, Jason; Brazee, Patricia L.; Hariri, Lida P.; Montesi, Sydney B.; Black, Katherine; Hla, Timothy; Kuo, Andrew; Cartier, Andréane; Engelbrecht, Eric; Christoffersen, Christina; Shea, Barry S.; Tager, Andrew M.; Medoff, Benjamin D.

doi:10.1165/rcmb.2020-0408oc

Cited by 25 publications

(25 citation statements)

References 41 publications

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“…In contrast, removal of fibrinolysis components, i.e., loss of tissue plasminogen activator or gain of PAI-1 both exacerbated fibrosis (94). Activation of PAR1 by thrombin is important in a modified bleomycin lung fibrosis model where bleomycin induced fibrosis is exacerbated by enhanced vascular leakage (16, 95). In the skin, fibrosis can be directly triggered by injection of fibrin into a tissue plasminogen activator deficient mouse, i.e., a setting of impaired fibrinolysis (20).…”

Section: Discussionmentioning

confidence: 99%

Extensive and Persistent Extravascular Dermal Fibrin Deposition Characterizes Systemic Sclerosis

Browning

Bhawan

Tseng

et al. 2023

Preprint

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Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive multiorgan fibrosis. While the cause of SSc remains unknown, a perturbed vasculature is considered a critical early step in the pathogenesis. Using fibrinogen as a marker of vascular leakage, we found extensive extravascular fibrinogen deposition in the dermis of early and late-stage patients with both limited and diffuse systemic sclerosis. Based on a timed series of excision wounds, retention on the fibrin deposit of the splice variant domain, fibrinogen αEC, indicated a recent event, while fibrin networks lacking the EC domain were older. Application of this timing tool to SSc revealed considerable heterogeneity in αEC domain distribution providing unique insight into disease activity. Intriguingly, the fibrinogen-αEC domain also accumulated in macrophages. These observations indicate that systemic sclerosis is characterized by ongoing vascular leakage resulting in extensive interstitial fibrin deposition that is either continually replenished and/or defective in fibrin clearance. Unresolved fibrin deposition might then incite chronic tissue remodeling.

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Section: Discussionmentioning

confidence: 99%

Extensive and Persistent Extravascular Dermal Fibrin Deposition Characterizes Systemic Sclerosis

Browning

Bhawan

Tseng

et al. 2023

Preprint

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“…In this study, disturbing SPHK1 expression in endothelial cells had no effect. In parallel, invalidation of the S1P receptor 1 gene in endothelial cells resulted in worsened fibrosis after bleomycin exposure [ 160 ]. Compared to controls, S1pr1-/- mice have increased vascular permeability and immune cell influx within the lung as well as coagulation activation.…”

Section: Extracellular Lipids As Important Regulators Of Fibrosis Pro...mentioning

confidence: 99%

“…Compared to controls, S1pr1-/- mice have increased vascular permeability and immune cell influx within the lung as well as coagulation activation. Interestingly, increased S1P/S1PR1 axis in ApoM overexpressing transgenic mice did not reduce experimental fibrosis compared with normal mice [ 160 ]. S1pr2 null mice exhibited less inflammation and fibrosis upon bleomycin compared with wild-type mice [ 161 ].…”

Section: Extracellular Lipids As Important Regulators Of Fibrosis Pro...mentioning

confidence: 99%

Extracellular Lipids in the Lung and Their Role in Pulmonary Fibrosis

Burgy

Loriod

Beltramo

et al. 2022

Cells

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Lipids are major actors and regulators of physiological processes within the lung. Initial research has described their critical role in tissue homeostasis and in orchestrating cellular communication to allow respiration. Over the past decades, a growing body of research has also emphasized how lipids and their metabolism may be altered, contributing to the development and progression of chronic lung diseases such as pulmonary fibrosis. In this review, we first describe the current working model of the mechanisms of lung fibrogenesis before introducing lipids and their cellular metabolism. We then summarize the evidence of altered lipid homeostasis during pulmonary fibrosis, focusing on their extracellular forms. Finally, we highlight how lipid targeting may open avenues to develop therapeutic options for patients with lung fibrosis.

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“…However, Knipe et al. 28 showed that ApoM Tg + mice that overexpressed S1P chaperone protein, apolipoprotein M (ApoM), or with increased circulating levels of S1P, a physiological signaling molecule that acts as a ligand for S1PR1–5, could not protect mice from bleomycin-induced PF. Tager et al.…”

Section: Introductionmentioning

confidence: 99%

S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung

Hao

Fu²,

Tai³

et al. 2023

Acta Pharmaceutica Sinica B

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Endothelial-Specific Loss of Sphingosine-1-Phosphate Receptor 1 Increases Vascular Permeability and Exacerbates Bleomycin-induced Pulmonary Fibrosis

Cited by 25 publications

References 41 publications

Extensive and Persistent Extravascular Dermal Fibrin Deposition Characterizes Systemic Sclerosis

Extensive and Persistent Extravascular Dermal Fibrin Deposition Characterizes Systemic Sclerosis

Extracellular Lipids in the Lung and Their Role in Pulmonary Fibrosis

S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung

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