New Therapeutic Targets in Idiopathic Pulmonary Fibrosis. Aiming to Rein in Runaway Wound-Healing Responses

Ahluwalia, Neil; Shea, Barry S.; Tager, Andrew M.

doi:10.1164/rccm.201403-0509pp

Cited by 212 publications

(191 citation statements)

References 145 publications

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“…Intra-tracheal BLC application leads to granulocytes influx, the granulocytes release reactive oxygen species (ROS) such as hydrogen peroxides (H 2 O 2 ), superoxide anion radical ( − O), and hydroxyl radicals ( − OH) by increasing the release of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, along with proteolytic enzymes, which cause DNA injury, peroxidation of lipids, oxidation of carbohydrates, and finally alterations in synthesis and degradation of lung prostaglandins [4]. Injury, inflammation, and alteration in cytokine release result in increased fibroblast activation and increased collagen production, while decreasing collagen degradation [5].…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats

et al. 2015

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We aimed to investigate the preventive effect of Infliximab (IFX), a tumor necrosis factor (TNF)-α inhibitor, on bleomycin (BLC)-induced lung fibrosis in rats. Rats were assigned into four groups as follows: I-BLC group, a single intra-tracheal BLC (2.5 mg/kg) was installed; II-control group, a single intra-tracheal saline was installed; III-IFX + BLC group, a single-dose IFX (7 mg/kg) was administered intraperitoneally (i.p.), 72 h before the intra-tracheal BLC installation; IV-IFX group, IFX (7 mg/kg) was administered alone i.p. on the same day with IFX + BLC group. All animals were sacrificed on the 14th day of BLC installation. Levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, interleukin (IL)-6, periostin, YKL-40, nitric oxide (NO) in rat serum were measured, as well as, myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity, and reduced glutathione (GSH), hydroxyproline, malondialdehyde (MDA) content in lung homogenates. Lung tissues were stained with hematoxylin and eosin (H&E) for quantitative histological evaluation. The inducible nitric oxide synthase (iNOS) expression and cell apoptosis in the lung tissues were determined quantitatively by immunohistochemical staining (INOS) and by TUNNEL staining, respectively. BLC installation worsened antioxidant status (such as SOD, CAT, GPx, GSH, MPO), while it increased the serum TNF-α, TGF-β, IL-6, periostin, YKL-40, and lipid peroxidation, and collagen deposition, measured by MDA and hydroxyproline, respectively. IFX pretreatment improved antioxidant status as well as BLC-induced lung pathological changes, while it decreased the TNF-α, TGF-β, IL-6, periostin, YKL-40, lipid peroxidation and collagen deposition. Finally, histological, immunohistochemical, and TUNNEL evidence also supported the ability of IFX to prevent BLC-induced lung fibrosis. The results of the present study indicate that IFX pretreatment can attenuate BLC-induced pulmonary fibrosis.

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Section: Introductionmentioning

confidence: 99%

Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats

et al. 2015

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“…Therefore, matrix and matrix-processing enzymes will provide promising novel drug targets for IPF. For instance, inhibition of the collagen cross-linking enzyme lysyl oxidase-like 2 (LOXL2) is currently investigated as an IPF treatment option in a phase II trial (8).…”

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confidence: 99%

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Staab-Weijnitz

Fernandez

Knüppel

et al. 2015

Am J Respir Crit Care Med

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Rationale: Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta).Objectives: To assess the expression and function of FKBP10 in IPF. Methods:We assessed FKBP10 expression in bleomycininduced lung fibrosis (using quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U.S. cohort, and performed Western blot analysis from 6 patients with IPF and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by endoplasmic reticulum stress or transforming growth factor-b 1 , was analyzed by small interfering RNA-mediated loss-of-function experiments, quantitative reverse transcriptase-polymerase chain reaction, Western blot, and quantification of secreted collagens in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF.Measurements and Main Results: FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68 1 macrophages. Transforming growth factor-b 1 , but not endoplasmic reticulum stress, induced FKBP10 expression in phLF. The small interfering RNA-mediated knockdown of FKBP10 attenuated expression of profibrotic mediators and effectors, including collagens I and V and a-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen secretion by phLF.Conclusions: FKBP10 might be a novel drug target for IPF.

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“…Aberrant or overexuberant wound healing responses to chronic lung injury are now thought to be responsible for the excessive fibroblast accumulation and extracellular matrix deposition that distort the lung's architecture and compromise its function in IPF (1,2). Better characterization of these abnormal responses to lung injury should provide a rich set of therapeutic targets for novel IPF therapies.…”

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confidence: 99%

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

Ahluwalia

Grasberger

Mugo

et al. 2016

Am J Respir Cell Mol Biol

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Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-b, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.Keywords: idiopathic pulmonary fibrosis; pathogenesis; fibroblast; invasion; migration Idiopathic pulmonary fibrosis (IPF) is a disease of great unmet medical need. Aberrant or overexuberant wound healing responses to chronic lung injury are now thought to be responsible for the excessive fibroblast accumulation and extracellular matrix deposition that distort the lung's architecture and compromise its function in IPF (1, 2). Better characterization of these abnormal responses to lung injury should provide a rich set of therapeutic targets for novel IPF therapies.The abnormal accumulation of fibroblasts is a central hallmark of fibrotic tissues, including the lung in IPF. In addition to fibroblast proliferation, fibroblast accumulation in pulmonary fibrosis appears to fundamentally depend on: (1) the migration of these cells to sites of tissue injury; and (2) their ability to invade extracellular matrix. Although migration

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New Therapeutic Targets in Idiopathic Pulmonary Fibrosis. Aiming to Rein in Runaway Wound-Healing Responses

Cited by 212 publications

References 145 publications

Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats

Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Fibrogenic Lung Injury Induces Non–Cell-Autonomous Fibroblast Invasion

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