Uncoupling of the profibrotic and hemostatic effects of thrombin in lung fibrosis

Shea, Barry S.; Probst, Clemens K.; Brazee, Patricia L.; Rotile, Nicholas J.; Blasi, Francesco; Weinreb, Paul H.; Black, Katharine E.; Sosnovik, David E.; Cott, Elizabeth M. Van; Violette, Shelia M.; Caravan, Peter; Tager, Andrew M.

doi:10.1172/jci.insight.86608

Cited by 71 publications

(55 citation statements)

References 75 publications

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“…During the infection, spirochetes are trapped within obliterative microvascular lesions in synovial tissue (Johnston et al, ) and in other tissues (Cadavid, ), and infection results in significant damage to the microvasculature (Duray & Steere, ; Lalosevic, Lalosevic, Stojsic‐Milosavljevic, & Stojsic, ; Lochhead et al, ). Vascular leakage is itself a profibrotic process (Shea et al, ). Additionally, B. burgdorferi binds to soluble fibronectin (Niddam et al, ) and fibronectin within the joint (Lin et al, ; Lin et al, ), resulting in inflammation at sites of vessel injury and induction of clot formation, a process that is regulated by plasma fibronectin (Wang, Gallant, & Ni, ).…”

Section: Discussionmentioning

confidence: 99%

“…During the infection, spirochetes are trapped within obliterative microvascular lesions in synovial tissue (Johnston et al, 1985) and in other tissues (Cadavid, 2006), and infection results in significant damage to the microvasculature Lalosevic, Lalosevic, Stojsic-Milosavljevic, & Stojsic, 2010;Lochhead et al, 2015). Vascular leakage is itself a profibrotic process (Shea et al, 2017). Additionally, B. burgdorferi binds to soluble fibronectin (Niddam et al, 2017) and…”

Section: Altered Early Response To Wounding Expression Signaturementioning

confidence: 99%

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Robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious,Borrelia burgdorferi‐induced Lyme arthritis

Lochhead

Arvikar

Aversa

et al. 2018

Cellular Microbiology

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In most patients with Lyme arthritis (LA), antibiotic therapy results in Borrelia burgdorferi pathogen elimination, tissue repair, and return to homeostasis. However, despite spirochetal killing, some patients develop proliferative synovitis, characterised by synovial hyperplasia, inflammation, vascular damage, and fibrosis that persists for months to several years after antibiotic treatment, called postinfectious LA. In this study, we characterised the transcriptomes of postinfectious LA patients' synovial tissue, the target tissue of the immune response. High-throughput RNA sequencing to a depth of ~30 million reads per sample was used to profile gene expression in synovial tissue from 14 patients with postinfectious LA, compared with eight patients with other types of chronic inflammatory arthritis and five with minimally inflammatory osteoarthritis (OA). Synovium from postinfectious LA and other inflammatory arthritides shared gene signatures associated with antigen presentation, innate immune responses, and cell-mediated immune activation, whereas these responses were diminished in OA synovium. Unique to postinfectious LA was a particularly robust interferon-gamma (IFNγ) signature. Moreover, this heightened IFNγ signature inversely correlated with expression of genes involved in repair of damaged tissue, including genes associated with stromal cell proliferation and differentiation, neovascularisation, and extracellular matrix synthesis, which were markedly suppressed in postinfectious LA. Transcriptional observations were confirmed by cytokine profiling, histologic analyses, and clinical correlations. We propose that in patients with postinfectious LA, overexpression of IFNγ in synovium prevents appropriate repair of tissue damaged by B. burgdorferi infection, blocking return to tissue homeostasis long after completion of antibiotic therapy and resolution of active infection.

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Section: Discussionmentioning

confidence: 99%

Section: Altered Early Response To Wounding Expression Signaturementioning

confidence: 99%

Robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious,Borrelia burgdorferi‐induced Lyme arthritis

Lochhead

Arvikar

Aversa

et al. 2018

Cellular Microbiology

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“…S1P was found to be elevated in idiopathic pulmonary fibrosis [31], human liver fibrosis [32] and is profibrotic in experimental models of lung fibrosis [33] mainly acting through S1P 2 and S1P 3 [34]. Interestingly, the profibrotic effects of thrombin [35][36][37] are independent of its role in hemostasis but dependent on the activation of protease-activated receptor 1 (PAR-1) [38]. However, for all of these ligands, the mechanistic connection between GPCR ligands, promotion of fibrosis and the potential role of YAP in this process is not completely understood.…”

Section: Introductionmentioning

confidence: 99%

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

et al. 2020

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Tissue fibrosis is a pathological condition characterized by uncontrolled fibroblast activation that ultimately leads to organ failure. The TGFβ1 pathway, one of the major players in establishment of the disease phenotype, is dependent on the transcriptional co-activators YAP/ TAZ. We were interested whether fibroblasts can be sensitized to TGFβ1 by activation of the GPCR/YAP/TAZ axis and whether this mechanism explains the profibrotic properties of diverse GPCR ligands. We found that LPA, S1P and thrombin cooperate in human dermal fibroblasts with TGFβ1 to induce extracellular matrix synthesis, myofibroblast marker expression and cytokine secretion. Whole genome expression profiling identified a YAP/ TAZ signature behind the synergistic profibrotic effects of LPA and TGFβ1. LPA, S1P and thrombin stimulation led to activation of the Rho-YAP axis, an increase of nuclear YAP-Smad2 complexes and enhanced expression of profibrotic YAP/Smad2-target genes. More generally, dermal, cardiac and lung fibroblast responses to TGFβ1 could be enhanced by increasing YAP nuclear levels (with GPCR ligands LPA, S1P, thrombin or Rho activator) and inhibited by decreasing nuclear YAP (with Rho inhibitor, forskolin, latrunculin B or 2deoxy-glucose). Thus, we present here a conceptually interesting finding that fibroblast responses to TGFβ1 can be predicted based on the nuclear levels of YAP and modulated by stimuli/treatments that change YAP nuclear levels. Our study contributes to better understanding of fibrosis as a complex interplay of signalling pathways and proposes YAP/TAZ as promising targets in the treatment of fibrosis.

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“…We previously reported MR probes and methods to quantify the burden of brosis in the lung, 31 inammation in the lung, 32 as well as vascular permeability in the context of IPF. 33,34 Our data indicate that improving the aldehyde reactivity and affinity of hydrazine-bearing gadolinium contrast agents translates to enhanced and prolonged accumulation in brosing lung tissue and improved specicity. We are currently expanding our library of allysine-reactive probes to determine the relationship of modifying the rate of reactivity on in vivo efficacy.…”

Section: Discussionmentioning

confidence: 81%

Improving the reactivity of hydrazine-bearing MRI probes for in vivo imaging of lung fibrogenesis

et al. 2020

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Uncoupling of the profibrotic and hemostatic effects of thrombin in lung fibrosis

Cited by 71 publications

References 75 publications

Robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious,Borrelia burgdorferi‐induced Lyme arthritis

Robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious,Borrelia burgdorferi‐induced Lyme arthritis

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

Improving the reactivity of hydrazine-bearing MRI probes for in vivo imaging of lung fibrogenesis

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