TRAIL-Dependent Resolution of Pulmonary Fibrosis

Habiel, David M.; Moreira, Ana Paula; Ismailoglu, Ugur B.; Dunleavy, Michael; Cavassani, Karen A.; Rooijen, Nico van; Coelho, Ana Lúcia; Hogaboam, Cory M.

doi:10.1155/2018/7934362

Cited by 6 publications

(4 citation statements)

References 54 publications

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“…First, preclinical trials often utilize mouse models of bleomycin induced pulmonary fibrosis, which is based on inflammation [196]. The second reason of failure of broad acting antiinflammatory molecules is that they also interact with potential antifibrotic properties of immune cells [197][198][199][200][201][202]. Finally, emerging evidence suggest that the etiology of acute exacerbation of IPF (AE-IPF) is different than that of slowly progressing IPF [203][204][205].…”

Section: Anti-inflammatory Trials In Ipfmentioning

confidence: 99%

Inflammation and immunity in IPF pathogenesis and treatment

Heukels

Moor

Thüsen

et al. 2019

Respiratory Medicine

333

231

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Idiopathic pulmonary fibrosis (IPF) is a progressive, and ultimately fatal, chronic interstitial lung disease characterized by enhanced extracellular matrix deposition. Repetitive alveolar epithelial injury triggers the early development of fibrosis. These injuries, in combination with dysregulated wound repair and fibroblast dysfunction, lead to ongoing tissue remodelling and fibrosis seen in end-stage pulmonary fibrosis. Although the exact etiology in IPF is unknown and probably diverse, all stages of fibrosis are accompanied by innate and adaptive immune responses. The role of inflammation as an important component in IPF etiology is controversial and sometimes seen as an epiphenomenon of fibrosis. This view is partly the result of negative multicenter trials of anti-inflammatory drugs for IPF treatment. However, new insights on the role of macrophages, the loss of Tcell and B-cell tolerance leading auto-immune responses in IPF, and the interaction of immune cells with (myo) fibroblasts have led to a slow change of this opinion. Clearly, more insight is needed to integrate basic immune mechanisms into translational research and finally new IPF therapies.In this concise review, we will focus on the role of our innate and adaptive immune system in the initiation and perpetuation of IPF pathobiology. Next, we will discuss how immune responses are influenced by current anti-fibrotic treatments, such as pirfenidone and nintedanib and end with an overview of recent and upcoming therapeutic trials that target and modulate our immune system in patients with IPF.

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Section: Anti-inflammatory Trials In Ipfmentioning

confidence: 99%

Inflammation and immunity in IPF pathogenesis and treatment

Heukels

Moor

Thüsen

et al. 2019

Respiratory Medicine

333

231

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“…To test the in vivo efficacy of quercetin in resolving fibrosis in aged mice, a bleomycin-induced lung injury model in C57BL/6 mice aged 12 months or older was employed. Before testing the effect of quercetin, we assessed if supplementation with FasL and TRAIL would be necessary, because we had previously observed depletion of TRAIL concentrations in the lungs of young mice after bleomycin exposure (27). Both the depletion of TRAIL and the depletion of FasL are known to exacerbate pulmonary lung injury and fibrosis (28,29).…”

Section: Quercetin Reverses Bleomycininduced Pulmonary Fibrosismentioning

confidence: 99%

Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis In Vivo

Hohmann

Habiel

Coelho

et al. 2019

Am J Respir Cell Mol Biol

Self Cite

156

121

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While cellular senescence may be a protective mechanism in modulating proliferative capacity, fibroblast senescence is now recognized as a key pathogenic mechanism in Idiopathic Pulmonary Fibrosis (IPF). In aged mice, abundance and persistence of apoptosis-resistant senescent fibroblasts play a central role in non-resolving lung fibrosis after bleomycin challenge. Therefore, we investigated whether quercetin can restore the susceptibility of senescent IPF fibroblasts to pro-apoptotic stimuli and mitigate bleomycin-induced pulmonary fibrosis in aged mice. Unlike senescent normal lung (NL) fibroblasts, IPF lung fibroblasts from patients with stable and rapidly progressing disease were highly resistant to Fas ligand (FasL) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Senescent IPF fibroblasts exhibited decreased expression of FasL and TRAIL receptors and caveolin-1, as well as increased AKT activation compared with senescent NL fibroblasts. Although, quercetin alone was not pro-apoptotic, it abolished the resistance to FasL- or TRAIL-induced apoptosis in IPF fibroblasts. Mechanistically, quercetin up regulated Fas and caveolin-1 expression, and modulated AKT activation. In vivo, quercetin reversed bleomycin-induced pulmonary fibrosis and attenuated lethality, weight loss, and the expression of pulmonary senescence markers p21 and p19-ARF and senescence-associated secretory phenotype (SASP) in aged mice. Collectively these data indicate that quercetin reverses the resistance to death ligand-induced apoptosis, by promoting FasL receptor and caveolin-1 expression, and inhibiting AKT activation, thus mitigating the progression of established pulmonary fibrosis in aged mice. Therefore, quercetin may be a viable therapeutic option for IPF and other age-related diseases that progress with the accumulation of senescent fibroblasts.

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“…Whereas modulating the related kinase activities, cytokine signaling, and protein homeostasis has come up with a productive portfolio of efficacious medications to treat fibrosis and cancer simultaneously, such interdisciplinary scientific interests across these two disease fields are currently going beyond the established therapeutic targets, inspiring innovative preclinical studies [2,51]. In this sense, while aberrant activation of the developmental biological pathway Wnt/β-catenin was recognized to facilitate cancer stem cells and pulmonary fibrosis [61,62], TNF related apoptosis-inducing ligand (TRAIL) signaling cascade is emerging as a key mediator for malignant cell death as well as myofibroblast inhibition [63]. Meanwhile, the lysophosphatidic acid (LPA) pathway is emerging as an important mediator in the pathogenesis of cancer and fibrosis; of note, the inhibitors of LPA-producing enzyme autotaxin and LPA receptors have showed an encouraging efficacy during phase II clinical trials in patients with pulmonary fibrosis [64,65].…”

Section: Perspectivementioning

confidence: 99%

Dually Efficacious Medicine Against Fibrosis and Cancer

Chen¹

2019

Medical Sciences

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Although there is a contemporary consensus of managing a severe disease with multi-targeted approach-based therapeutic combinations, it should not be ignored that certain patho-biological pathways are shared by distinct medical conditions and can be exploited to develop an exceptional type of medication conferring a dual efficacy. This article thus presents a spectrum of emerging molecular targets that substantially contribute to the pathogenesis of both fibrotic and neoplastic disorders, including kinase activities, cytokine cascades, and protein dynamics among others. Moreover, recently approved therapeutic agents in this regard have been sorted out to corroborate the drug’s ability upon targeting each one of these molecular pathways to treat fibrosis and cancer simultaneously. It not only streamlines an overlapping mechanistic profile in the pathogenesis across these two medical conditions, but also inspires clinicians and pharmaceutical innovation to tackle concomitant diseases, such as fibrosis and cancer, with an optimally efficacious medication.

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TRAIL-Dependent Resolution of Pulmonary Fibrosis

Cited by 6 publications

References 54 publications

Inflammation and immunity in IPF pathogenesis and treatment

Inflammation and immunity in IPF pathogenesis and treatment

Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis In Vivo

Dually Efficacious Medicine Against Fibrosis and Cancer

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