Cangrelor alleviates bleomycin-induced pulmonary fibrosis by inhibiting platelet activation in mice

Zhan, Tianzuo; Wei, Taofeng; Dong, Lingjun; Wang, Qi; Wu, Zixiang; Yan, Qing; Zhang, Weiping; Lu, Yun-Bi; Wu, Ming

doi:10.1016/j.molimm.2020.01.017

Cited by 19 publications

(9 citation statements)

References 40 publications

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“…[283][284][285] Increase of PF4 has been reported upon treatment of bleomycin, a drug that causes fibrosis, in lung tissue. 286 In recent years, more evidence in line with this initial study have been reported. PF4 induces a pro-inflammatory and pro-fibrotic phenotype in monocyte-derived DCs, increasing ECM production, and inducing myofibroblast differentiation.…”

Section: Pf4 and Fibrosissupporting

confidence: 69%

Role of platelet factor 4 in arteriovenous fistula maturation failure: What do we know so far?

et al. 2022

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The rate of arteriovenous fistula (AVF) maturation failure remains unacceptably high despite continuous efforts on technique improvement and careful pre-surgery planning. In fact, half of all newly created AVFs are unable to be used for hemodialysis (HD) without a salvage procedure. While vascular stenosis in the venous limb of the access is the culprit, the underlying factors leading to vascular narrowing and AVF maturation failure are yet to be determined. We have recently demonstrated that AVF non-maturation is associated with post-operative medial fibrosis and fibrotic stenosis, and post-operative intimal hyperplasia (IH) exacerbates the situation. Multiple pathological processes and signaling pathways are underlying the stenotic remodeling of the AVF. Our group has recently indicated that a pro-inflammatory cytokine platelet factor 4 (PF4/CXCL4) is upregulated in veins that fail to mature after AVF creation. Platelet factor 4 is a fibrosis marker and can be detected in vascular stenosis tissue, suggesting that it may contribute to AVF maturation failure through stimulation of fibrosis and development of fibrotic stenosis. Here, we present an overview of the how PF4-mediated fibrosis determines AVF maturation failure.

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Section: Pf4 and Fibrosissupporting

confidence: 69%

Role of platelet factor 4 in arteriovenous fistula maturation failure: What do we know so far?

et al. 2022

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“…The Gene Ontology enrichment analysis suggested MC0 participated in collagen fibril organization and ECM organization (Fig. S3B ), and the QuSAGE analysis of enriched pathways showed that genes related to ECM–receptor interaction and platelet activation that are associated with fibrosis were upregulated in MC0 26 – 28 (Fig. S3C ).…”

Section: Resultsmentioning

confidence: 99%

Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration

Zhang,

Xiao,

et al. 2024

Bone Res

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Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26RtdTomato mice to lethally irradiated Ackr1−/− mice (Ackr1−/− chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.

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“…Platelets highly express BCL-XL and are susceptible to death after ABT-263 treatment ( 34 ). However, platelets from patients with IPF have been shown to have increased activity compared with healthy patients ( 60 ), and their inhibition was antifibrotic in a mouse model of pulmonary fibrosis ( 61 ). Pulmonary hypertension, a common comorbidity in PF-ILD, has a prevalence of approximately 30%–50% in patients with IPF ( 62 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis

Cooley¹,

Javkhlan²,

Wilson³

et al. 2023

JCI Insight

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Patients with progressive fibrosing interstitial lung diseases (PF-ILDs) carry a poor prognosis and have limited therapeutic options. A hallmark feature is fibroblast resistance to apoptosis, leading to their persistence, accumulation, and excessive deposition of extracellular matrix. A complex balance of the B cell lymphoma 2 (BCL-2) protein family controlling the intrinsic pathway of apoptosis and fibroblast reliance on antiapoptotic proteins has been hypothesized to contribute to this resistant phenotype. Examination of lung tissue from patients with PF-ILD (idiopathic pulmonary fibrosis and silicosis) and mice with PF-ILD (repetitive bleomycin and silicosis) showed increased expression of antiapoptotic BCL-2 family members in α–smooth muscle actin–positive fibroblasts, suggesting that fibroblasts from fibrotic lungs may exhibit increased susceptibility to inhibition of antiapoptotic BCL-2 family members BCL-2, BCL-XL, and BCL-W with the BH3 mimetic ABT-263. We used 2 murine models of PF-ILD to test the efficacy of ABT-263 in reversing established persistent pulmonary fibrosis. Treatment with ABT-263 induced fibroblast apoptosis, decreased fibroblast numbers, and reduced lung collagen levels, radiographic disease, and histologically evident fibrosis. Our studies provide insight into how fibroblasts gain resistance to apoptosis and become sensitive to the therapeutic inhibition of antiapoptotic proteins. By targeting profibrotic fibroblasts, ABT-263 offers a promising therapeutic option for PF-ILDs.

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Cangrelor alleviates bleomycin-induced pulmonary fibrosis by inhibiting platelet activation in mice

Cited by 19 publications

References 40 publications

Role of platelet factor 4 in arteriovenous fistula maturation failure: What do we know so far?

Role of platelet factor 4 in arteriovenous fistula maturation failure: What do we know so far?

Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration

Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis

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