Pirfenidone Inhibits Lung Allograft Fibrosis through L-Arginine–Arginase Pathway

Liu, Hanzhong; Drew, Peter A.; Gaugler, Andrew; Cheng, Yanping; Visner, Gary

doi:10.1111/j.1600-6143.2005.00876.x

Cited by 65 publications

(65 citation statements)

References 30 publications

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“…Arginase has previously been shown to be involved in the development of PHT and lung fibrosis (9,25,29,32,44,63). Using repeated intraperitoneal administration of bleomycin in neonatal rats as a model of chronic neonatal lung injury and PHT, we report increased expression of arginase I, arginase II, and NOS2 in the bleomycin-exposed lung.…”

Section: Discussionmentioning

confidence: 79%

“…Arginases also regulate nitric oxide (NO) production by controlling substrate L-arginine availability for NO synthases (NOSs) (46). There is accumulating evidence that arginase activity contributes to the development of pulmonary fibrosis and pulmonary hypertension (PHT) (9,14,25,29,32,63).PHT is a common complication of moderate-severe bronchopulmonary dysplasia (BPD), a chronic lung disease affecting extremely premature infants (6). The underlying pathogenesis of BPD is complex and multifactorial (39).…”

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confidence: 99%

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Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Grasemann

Dhaliwal

Ivanovska

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycininduced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension. nitric oxide; oxidative stress; chronic lung disease ARGINASES METABOLIZE L-ARGININE to form L-ornithine and urea. L-Ornithine is the precursor for the production of polyamines and collagen, which have been implicated in tissue repair and remodeling, respectively. Arginases also regulate nitric oxide (NO) production by controlling substrate L-arginine availability for NO synthases (NOSs) (46). There is accumulating evidence that arginase activity contributes to the development of pulmonary fibrosis and pulmonary hypertension (PHT) (9,14,25,29,32,63).PHT is a common complication of moderate-severe bronchopulmonary dysplasia (BPD), a chronic lung disease affecting extremely premature infants (6). The underlying pathogenesis of BPD is complex and multifactorial (39). Previous studies from our group have established a model of repeated systemic bleomycin injection in neonatal rats that results in lung injury mimicking characteristics typical of BPD. This model is a useful tool to help understand mechanisms contributing to lung development and remodeling (31) but also to study the effects of therapeutic interventions aimed at preventing lung parenchymal and vascular injury (31,50,56).The chemotherapeutic agent bleomycin sulfate causes a pulmonary inflammatory and fibrotic response in rodents when instilled as a single intratracheal dose (27) or by repeated intraperitoneal injection (3). Bleomycin-induced lung injury is characterized by induction of proinflammatory cytokines (18), influx of macrophages and other inflammatory cells (23), "emphysematous" lung morphology, and severe PHT (49, 60). Herein, we report that arginase expression is greatly increased in the lungs of bleomycin-exposed neonatal rats and that concomitant treatment with an arginase inhibitor, ami...

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Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Grasemann

Dhaliwal

Ivanovska

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Increased arginase expression was demonstrated in bleomycin-induced lung fibrosis in mice (Endo et al, 2003), and arginase activity was associated with lung collagen content in a model of allograft fibrosis in rats (Liu et al, 2005). In addition, repeated allergen challenge-induced lung hydroxyproline increase in guinea pigs was inhibited by inhaled ABH .…”

Section: Discussionmentioning

confidence: 79%

Arginase Inhibition Prevents Inflammation and Remodeling in a Guinea Pig Model of Chronic Obstructive Pulmonary Disease

Pera

Zuidhof

Smit

et al. 2014

J Pharmacol Exp Ther

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Airway inflammation and remodeling are major features of chronic obstructive pulmonary disease (COPD), whereas pulmonary hypertension is a common comorbidity associated with a poor disease prognosis. Recent studies in animal models have indicated that increased arginase activity contributes to features of asthma, including allergeninduced airway eosinophilia and mucus hypersecretion. Although cigarette smoke and lipopolysaccharide (LPS), major risk factors for COPD, may increase arginase expression, the role of arginase in COPD is unknown. This study aimed to investigate the role of arginase in pulmonary inflammation and remodeling using an animal model of COPD. Guinea pigs were instilled intranasally with LPS or saline twice weekly for 12 weeks and pretreated by inhalation of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or vehicle. Repeated LPS exposure increased lung arginase activity, resulting in increased L-ornithine/L-arginine and L-ornithine/L-citrulline ratios. Both ratios were reversed by ABH. ABH inhibited the LPS-induced increases in pulmonary IL-8, neutrophils, and goblet cells as well as airway fibrosis. Remarkably, LPS-induced right ventricular hypertrophy, indicative of pulmonary hypertension, was prevented by ABH. Strong correlations were found between arginase activity and inflammation, airway remodeling, and right ventricular hypertrophy. Increased arginase activity contributes to pulmonary inflammation, airway remodeling, and right ventricular hypertrophy in a guinea pig model of COPD, indicating therapeutic potential for arginase inhibitors in this disease.

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“…In support of this, the profibrotic factor TGF-b has been shown to induce arginase activity in mouse lung and fibroblasts [45]. Moreover, increased expression of arginases I and II was closely associated with increased collagen I and hydroxyproline expression in bleomycin-induced lung fibrosis in mice [27,46].…”

Section: Discussionmentioning

confidence: 88%

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

Maarsingh

Dekkers²,

Zuidhof³

et al. 2011

Eur Respir J

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Airway remodelling, characterised by increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia and mucus gland hypertrophy, is a feature of chronic asthma. Increased arginase activity could contribute to these features via increased formation of polyamines and L-proline downstream of the arginase product L-ornithine, and via reduced nitric oxide synthesis.Using the specific arginase inhitibor 2(S)-amino-6-boronohexanoic acid (ABH), we studied the role of arginase in airway remodelling using a guinea pig model of chronic asthma. Ovalbuminsensitised guinea pigs were treated with ABH or PBS via inhalation before each of 12 weekly allergen or saline challenges, and indices of arginase activity, and airway remodelling, inflammation and responsiveness were studied 24 h after the final challenge.Pulmonary arginase activity of repeatedly allergen-challenged guinea pigs was increased. Allergen challenge also increased ASM mass and maximal contraction of denuded tracheal rings, which were prevented by ABH. ABH also attenuated allergen-induced pulmonary hydroxyproline (fibrosis) and putrescine, mucus gland hypertrophy, goblet cell hyperplasia, airway eosinophilia and interleukin-13, whereas an increased L-ornithine/L-citrulline ratio in the lung was normalised. Moreover, allergen-induced hyperresponsiveness of perfused tracheae was fully abrogated by ABH.These findings demonstrate that arginase is prominently involved in allergen-induced airway remodelling, inflammation and hyperresponsiveness in chronic asthma.

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Pirfenidone Inhibits Lung Allograft Fibrosis through L-Arginine–Arginase Pathway

Cited by 65 publications

References 30 publications

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Arginase Inhibition Prevents Inflammation and Remodeling in a Guinea Pig Model of Chronic Obstructive Pulmonary Disease

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

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