Cellular FLICE-like Inhibitory Protein Deviates Myofibroblast Fas-Induced Apoptosis Toward Proliferation during Lung Fibrosis

Golan-Gerstl, Regina; Wallach-Dayan, Shulamit B.; Zisman, Philip; Cardoso, Wellington V.; Goldstein, Ronald H.; Breuer, Raphael

doi:10.1165/rcmb.2010-0284rc

Cited by 51 publications

(75 citation statements)

References 74 publications

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“…Indeed, one recent study showed that FLIP induction prevents embryonic fibroblast apoptosis induced by TNF-a (48). Another report recently showed c-FLIP expression in the fibroblastic foci of IPF biopsies while demonstrating increased c-FLIP expression in IPF fibroblasts (49). Moreover, loss of c-FLIP increased the sensitivity of fibroblasts to apoptosis (49).…”

Section: Discussionmentioning

confidence: 97%

“…Another report recently showed c-FLIP expression in the fibroblastic foci of IPF biopsies while demonstrating increased c-FLIP expression in IPF fibroblasts (49). Moreover, loss of c-FLIP increased the sensitivity of fibroblasts to apoptosis (49). In contrast, another study argued against a role for c-FLIP as a mechanism of apoptosis resistance in IPF fibroblasts by demonstrating that c-FLIP was expressed in the epithelium overlying fibroblastic foci but not in the fibroblasts themselves (46).…”

Section: Discussionmentioning

confidence: 99%

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X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (XIAP) has been suggested by prior studies showing that (1) XIAP is localized to fibroblastic foci in IPF tissue and (2) prostaglandin E 2 suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-b1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-b1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fasmediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.Keywords: myofibroblast; idiopathic pulmonary fibrosis; inhibitor of apoptosis; lung fibrosis; apoptosis Mesenchymal cells display a dynamic spectrum of phenotypes ranging between an undifferentiated state (fibroblast) and a differentiated state (myofibroblast) (1, 2). Although these effector cells are essential for the homeostatic reestablishment of normal architecture and function after tissue injury, the persistence of these cells is associated with fibrosis (3, 4). The resolution phase of normal wound repair coincides with the reduction of fibroblast numbers by apoptosis, but the triggers of apoptosis in normal wound repair and the mechanisms underlying the persistence of fibroblasts during fibrotic wound repair remain poorly understood (5, 6). The profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 have been found to promote resistance to apoptotic stimuli in fibroblasts, and the antifibrotic lipid mediator prostaglandin (PG)E 2 has been shown to increase the responsiveness of these cells to apoptotic stimuli, supporting a role for dysregulation of fibroblast apoptosis in the pathogenesis of fibrosis (7-12).Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology that is characterized by progressive alveolar fibrosis (13,14). The overall prognosis of patie...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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“…55,70,71 An accumulating body of literature demonstrates that lung fibroblasts and myofibroblasts in both mouse fibrosis models and IPF acquire an apoptosis-resistant phenotype. 41,48,55,59,70,71 Several mechanisms by which myofibroblasts evade apoptosis have been identified, 72 and several common mechanistic themes have emerged. First, soluble profibrotic mediators that activate myofibroblasts, such as TGF-b1, also promote resistance to apoptosis.…”

Section: Role Of Apoptosis In Removing Myofibroblastsmentioning

confidence: 99%

“…73,74 Third, endogenous inhibitors of apoptosis, such as Fas-like IL 1b-converting enzymeeinhibitory protein and X-linked inhibitor of apoptosis, are induced by soluble profibrotic mediators and expressed at increased levels in fibrotic lung fibroblasts. 48,56,59 Fourth, the composition and biomechanical properties of the ECM can modulate fibroblast resistance to apoptosis. 41,75 Fifth, epigenetic alterations, such as methylation of the Thy-1 promoter in fibroblastic foci of IPF, have been linked to resistance to apoptosis.…”

Section: Role Of Apoptosis In Removing Myofibroblastsmentioning

confidence: 99%

Mechanisms of Lung Fibrosis Resolution

Glasser

Hagood

Wong

et al. 2016

The American Journal of Pathology

112

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“…In this study, we employed western blot analysis and found that ADSCs inhibited tunica albuginea MFs activation, which was indicated by a time-dependent decrease in αSMA expression. Apoptosis induced by loss of adhesion or adhesion-mediated signalling (termed 'anoikis') is a main pathway of tunica albuginea MFs clearance (44). Although the precise mechanism of myofibroblast apoptosis in the resolution of wound healing and tissue repair are not well defined, anoikis is likely a relevant model to study apoptotic mechanisms since cell adhesion and biomechanical tension unloading appear to play important roles in this physiological (45).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of penile tunica albuginea myofibroblasts activity by adipose‑derived stem cells

et al. 2017

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Abstract. The activation of tunica albuginea myofibroblasts (MFs) serves an essential role in Peyronie's disease (PD). Increasing evidence has reported that adipose tissue-derived stem cells (ADSCs) have been demonstrated to attenuate the symptoms of PD in animal models. However, the mechanisms of the antifibrotic effects of ADSCs in PD remain to be fully elucidated. In the present study, the inhibitory effects and possible mechanism of ADSCs on the activation of MFs derived from rat penile tunica albuginea were investigated. ADSCs were obtained from the paratesticular fat of Sprague Dawley rats. MFs were transformed from rat penile tunica albuginea fibroblasts through stimulation with 5 ng/ml tumor growth factor-β1. Transwell cell cultures were adopted for co-culture of ADSCs and MFs. Western blot analysis was used to assess changes in the expression levels of α smooth muscle actin (αSMA), collagen I, phosphorylated (p)-SMAD family member 2 (Smad2), Smad2, ras homolog family member A (RhoA), Rho associated coiled-coil containing protein kinase (ROCK)1 and ROCK2, caspase3, caspase9, and matrix metalloproteinases (MMPs). Collagen gel assays were used to assess cell contractility. Additionally, the concentration of hydroxyproline in the culture medium was detected using commercially available kits. It was demonstrated that ADSCs reduced the expression of αSMA and collagen I of MFs. Furthermore, p-Smad2, RhoA, ROCK1 and ROCK2 expression was significantly reduced in the MFs+ADSCs group compared with that in the MFs-only culture, while the expression of MMPs (MMP2, MMP3, MMP9 and MMP13) and caspases (caspase3 and caspase9) was upregulated. In addition, ADSCs were able to downregulate the concentration of hydroxyproline in the culture medium of MFs and reverse the contraction of MFs. Collectively, these results suggested that ADSCs inhibited the activation of MFs, decreased collagen production, and suppressed the contraction of myofibroblasts, via Smad and RhoA/ROCK signaling pathways. Furthermore, ADSCs reduced the deposition of collagen and promoted the apoptosis of MFs via MMPs, and caspases. Accordingly, the application of ADSCs may provide a novel therapeutic strategy for PD.

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Cellular FLICE-like Inhibitory Protein Deviates Myofibroblast Fas-Induced Apoptosis Toward Proliferation during Lung Fibrosis

Cited by 51 publications

References 74 publications

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Mechanisms of Lung Fibrosis Resolution

Inhibition of penile tunica albuginea myofibroblasts activity by adipose‑derived stem cells

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