Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge

Hirano, Atsushi; Kanehiro, Arihiko; Ono, Katsuichiro; Ito, Wataru; Yoshïda, Akio; Okada, Chiharu; Nakashima, Hiromi; Tanimoto, Yasushi; Kataoka, Masao; Gelfand, Erwin W.; Tanimoto, Mitsune

doi:10.1165/rcmb.2005-0452oc

Cited by 63 publications

(40 citation statements)

References 56 publications

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“…Recently, Leung and coworkers demonstrated that inhibition of TGF-b1 receptor kinase reversed bronchial hyperreactivity in a murine model of allergic lung inflammation (51). Similar results were obtained by Hirano and colleagues with pirfenidone, an antifibrotic agent (52), and by Nakao and coworkers using transgenic mice that overexpress SMAD7, an inhibitor of TGF-b1 signaling (53). Lee and colleagues (54) demonstrated that IL-13-mediated pulmonary fibrosis was mediated through TGF-b1, as did FichtnerFeigl and coworkers (55).…”

Section: Discussionsupporting

confidence: 58%

A Functional and Regulatory Map of Asthma

Novershtern

Barnett-Itzhaki²,

Manor³

et al. 2008

Am J Respir Cell Mol Biol

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The prevalence and morbidity of asthma, a chronic inflammatory airway disease, is increasing. Animal models provide a meaningful but limited view of the mechanisms of asthma in humans. A systemslevel view of asthma that integrates multiple levels of molecular and functional information is needed. For this, we compiled a gene expression compendium from five publicly available mouse microarray datasets and a gene knowledge base of 4,305 gene annotation sets. Using this collection we generated a high-level map of the functional themes that characterize animal models of asthma, dominated by innate and adaptive immune response. We used Module Networks analysis to identify co-regulated gene modules. The resulting modules reflect four distinct responses to treatment, including early response, general induction, repression, and IL-13-dependent response. One module with a persistent induction in response to treatment is mainly composed of genes with suggested roles in asthma, suggesting a similar role for other module members. Analysis of IL-13-dependent response using protein interaction networks highlights a role for TGF-b1 as a key regulator of asthma. Our analysis demonstrates the discovery potential of systems-level approaches and provides a framework for applying such approaches to asthma.Keywords: house dust mite; IL-13; ovalbumin; systems biology; TGF-b Asthma is a chronic lung disease characterized by airway inflammation, hyperresponsiveness, remodeling, and obstruction (1). The lung phenotype in asthma is believed to be determined by the interaction of the environment with the patient's genetic background (2). This interaction leads to a dramatic change in the airway microenvironment that includes activation of inflammatory pathways, recruitment of immune cells that are not usually present in the airway, and a dramatic change in the phenotype of airway resident cells. While individual changes in many of these factors may generate components of the asthmatic phenotype, it is the converging effects of these pathways on recruited and altered cells that determine the patient's disease.The advent of high-throughput technologies for gene and protein profiling has greatly improved our ability to characterize the behavior of genes and proteins in health and disease. Using animal models of allergic airway disease, investigators applied DNA microarrays to identify potential regulators of asthmatic airway inflammation such as C5 (3), ARG1 (4), ADAM8 (5), SPRR2 (6) as well as to explore the pathways activated by IL13 and STAT6 during the development of allergen-induced lung inflammation (7-9). Transcriptional analysis of the response to IL-13, allergen challenge, syncytial virus infection, and corticosteroids in epithelial cells identified multiple and rarely overlapping genes (10-14). While many of these studies used elegant experimental approaches to dissect pathways and to identify and validate potential novel key regulatory molecules, the majority of their insights were obtained using statistical methods that select...

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Section: Discussionsupporting

confidence: 58%

A Functional and Regulatory Map of Asthma

Novershtern

Barnett-Itzhaki²,

Manor³

et al. 2008

Am J Respir Cell Mol Biol

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“…Specific therapies against oxidative stress responses in ILD are being developed (26), thus defining biomarkers that are predictive of disease progression or responsive to specific therapies will be a significant advance in the field. Two drugs, pirfenidone and nintedanib, were recently approved drugs for IPF, the most prevalent and aggressive form of ILD; interestingly, pirfenidone seems to mediate its beneficial effects, in part, by modulating inflammatory responses and oxidative stress (43)(44)(45)(46). This will afford opportunities for the development of precision/personalized approaches to treatment, and more targeted therapeutics for this disease.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Modifications of Protein Tyrosyl Residues Are Increased in Plasma of Human Subjects with Interstitial Lung Disease

Pennathur

Vivekanandan-Giri²,

Locy

et al. 2016

Am J Respir Crit Care Med

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Rationale: Interstitial lung diseases (ILDs) are associated with oxidative stress. Plasma biomarkers that are directly linked to oxidative stress responses in this disease have not been identified. Stable oxidation products of tyrosine residues in proteins may reflect the oxidative microenvironment in the lung or a systemic inflammatory state.Objectives: To determine if levels of protein tyrosine oxidation are elevated in plasma of patients with ILD compared with an age-and sex-matched healthy control cohort.Methods: Three tyrosine oxidation products (3-chlorotyrosine, 3-nitrotyrosine, and o,o9-dityrosine) were quantified by tandem mass spectrometry in cellular models, a mouse model of injuryinduced fibrosis, and in plasma of healthy control subjects and patients with ILD (n = 42 in each group).Measurements and Main Results: Plasma levels of 3-chlorotyrosine, 3-nitrotyrosine, and o,o9-dityrosine were markedly elevated in patients with ILD compared with control subjects with receiver operating characteristic curves separating these groups of 0.872, 0.893, and 0.997, respectively. In a murine model of lung fibrosis, levels of all three oxidative tyrosine modifications were increased in plasma and lung tissue. Cellular models support a critical role for a heme peroxidase and enzymatic sources of reactive oxygen species in the generation of these oxidized products.Conclusions: We demonstrate an increase in oxidized tyrosine moieties within proteins in the circulating plasma of patients with ILD. These data support the potential for development of oxidative stress-related biomarkers in early diagnosis, prognostication, and/or in evaluating responsiveness to emerging therapies for ILD.

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“…Pirfenidone has also been demonstrated to reduce markers of oxidative stress in animal models, including lipid peroxidation and advanced lipoxidation end products, and superoxide dismutase and myeloperoxidase activity (74,75). In studies on cells in vitro, pirfenidone has been shown to inhibit multiple profibrotic behaviors of fibroblasts, including their proliferation, differentiation to myofibroblasts, and synthesis of collagen, suggesting that at least some of pirfenidone's antifibrotic activity is attributable to its actions on these cells (70,72,(75)(76)(77) …”

Section: Pirfenidonementioning

confidence: 99%

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

Ahluwalia

Shea

Tager

2014

Am J Respir Crit Care Med

212

176

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Idiopathic pulmonary fibrosis (IPF) is a devastating disease, with a median survival as short as 3 years from the time of diagnosis and no pharmacological therapies yet approved by the U.S. Food and Drug Administration. To address the great unmet need for effective IPF therapy, a number of new drugs have recently been, or are now being, evaluated in clinical trials. The rationales for most of these therapeutic candidates are based on the current paradigm of IPF pathogenesis, in which recurrent injury to the alveolar epithelium is believed to drive aberrant wound healing responses, resulting in fibrosis rather than repair. Here we discuss drugs in recently completed or currently ongoing phase II and III IPF clinical trials in the context of their putative mechanisms of action and the aberrant repair processes they are believed to target: innate immune activation and polarization, fibroblast accumulation and myofibroblast differentiation, or extracellular matrix deposition and stiffening. Placed in this context, the positive results of recently completed trials of pirfenidone and nintedanib, and results that will come from ongoing trials of other agents, should provide valuable insights into the still-enigmatic pathogenesis of this disease, in addition to providing benefits to patients with IPF.

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Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge

Cited by 63 publications

References 56 publications

A Functional and Regulatory Map of Asthma

A Functional and Regulatory Map of Asthma

Oxidative Modifications of Protein Tyrosyl Residues Are Increased in Plasma of Human Subjects with Interstitial Lung Disease

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

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