Bleomycin-induced pulmonary fibrosis is attenuated by a monoclonal antibody targeting HER2

2007 ◽  
Vol 103 (6) ◽  
pp. 2077-2083 ◽  
Author(s):  
Jihane A. Faress ◽  
David E. Nethery ◽  
Elizabeth F. O. Kern ◽  
Rosana Eisenberg ◽  
Frank J. Jacono ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Morphological Changes ◽  
Beneficial Effects ◽  
Significant Survival ◽  
Lung Injury Model ◽  
Pharmacological Blockade ◽  
Her2 Signaling

The importance of HER2/HER3 signaling in decreasing the effects of lung injury was recently demonstrated. Transgenic mice unable to signal through HER2/HER3 had significantly less bleomycin-induced pulmonary fibrosis and showed a survival benefit. Based on these data, we hypothesized that pharmacological blockade of HER2/HER3 in vivo in wild-type mice would have the same beneficial effects. We tested this hypothesis in a bleomycin lung injury model using 2C4, a monoclonal antibody directed against HER2 that blocks HER2/HER3 signaling. The administration of 2C4 before injury decreased the effects of bleomycin at days 15 and 21 after injury. HER2/HER3 blockade resulted in less collagen deposition (362.8 ± 37.9 compared with 610.5 ± 27.1 μg/mg; P = 0.03) and less lung morphological changes (injury score of 1.99 ± 1.55 vs. 3.90 ± 0.76; P < 0.04). In addition, HER2/HER3 blockade resulted in a significant survival advantage with 50% vs. 25% survival at 30 days ( P = 0.04). These results confirm that HER2 signaling can be pharmacologically targeted to reduce lung fibrosis and remodeling after injury.

scholarly journals Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation

2020 ◽  
Author(s):  
Ting Gao ◽  
Mingdong Hu ◽  
Xiaopeng Zhang ◽  
Hongzhen Li ◽  
Lin Zhu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Lung Injury ◽  
Complement Activation ◽  
Suppressive Effect ◽  
Lectin Pathway ◽  
Highly Pathogenic ◽  
N Protein ◽  
Promising Target

AbstractAn excessive immune response contributes to SARS-CoV, MERS-CoV and SARS-CoV-2 pathogenesis and lethality, but the mechanism remains unclear. In this study, the N proteins of SARS-CoV, MERS-CoV and SARS-CoV-2 were found to bind to MASP-2, the key serine protease in the lectin pathway of complement activation, resulting in aberrant complement activation and aggravated inflammatory lung injury. Either blocking the N protein:MASP-2 interaction or suppressing complement activation can significantly alleviate N protein-induced complement hyper-activation and lung injury in vitro and in vivo. Complement hyper-activation was also observed in COVID-19 patients, and a promising suppressive effect was observed when the deteriorating patients were treated with anti-C5a monoclonal antibody. Complement suppression may represent a common therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.One Sentence SummaryThe lectin pathway of complement activation is a promising target for the treatment of highly pathogenic coronavirus induced pneumonia.

scholarly journals Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury

2013 ◽  
Vol 305 (11) ◽  
pp. L844-L855 ◽  
Author(s):  
Ming-Yuan Jian ◽  
Mikhail F. Alexeyev ◽  
Paul E. Wolkowicz ◽  
Jaroslaw W. Zmijewski ◽  
Judy R. Creighton
Keyword(s):  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Ex Vivo ◽  
Endothelial Permeability ◽  
Beneficial Effects ◽  
Isolated Lung

Acute lung injury secondary to sepsis is a leading cause of mortality in sepsis-related death. Present therapies are not effective in reversing endothelial cell dysfunction, which plays a key role in increased vascular permeability and compromised lung function. AMP-activated protein kinase (AMPK) is a molecular sensor important for detection and mediation of cellular adaptations to vascular disruptive stimuli. In this study, we sought to determine the role of AMPK in resolving increased endothelial permeability in the sepsis-injured lung. AMPK function was determined in vivo using a rat model of endotoxin-induced lung injury, ex vivo using the isolated lung, and in vitro using cultured rat pulmonary microvascular endothelial cells (PMVECs). AMPK stimulation using N1-(α-d-ribofuranosyl)-5-aminoimidizole-4-carboxamide or metformin decreased the LPS-induced increase in permeability, as determined by filtration coefficient ( Kf) measurements, and resolved edema as indicated by decreased wet-to-dry ratios. The role of AMPK in the endothelial response to LPS was determined by shRNA designed to decrease expression of the AMPK-α1 isoform in capillary endothelial cells. Permeability, wounding, and barrier resistance assays using PMVECs identified AMPK-α1 as the molecule responsible for the beneficial effects of AMPK in the lung. Our findings provide novel evidence for AMPK-α1 as a vascular repair mechanism important in the pulmonary response to sepsis and identify a role for metformin treatment in the management of capillary injury.

scholarly journals Hyperoxia-induced neonatal rat lung injury involves activation of TGF-β and Wnt signaling and is protected by rosiglitazone

2009 ◽  
Vol 296 (6) ◽  
pp. L1031-L1041 ◽  
Author(s):  
Chiranjib Dasgupta ◽  
Reiko Sakurai ◽  
Ying Wang ◽  
Pinzheng Guo ◽  
Namasivayam Ambalavanan ◽  
...  
Keyword(s):  
Lung Injury ◽  
Wnt Signaling ◽  
Transforming Growth Factor ◽  
Very Low Birth Weight ◽  
Morphological Changes ◽  
Smooth Muscle Actin ◽  
Neonatal Rat ◽  
Respiratory Morbidity ◽  
Rat Lung

Despite tremendous technological and therapeutic advances, bronchopulmonary dysplasia (BPD) remains a leading cause of respiratory morbidity in very low birth weight infants, and there are no effective preventive and/or therapeutic options. We have previously reported that hyperoxia-induced neonatal rat lung injury might be prevented by rosiglitazone (RGZ). Here, we characterize 1) perturbations in wingless/Int (Wnt) and transforming growth factor (TGF)-β signaling, and 2) structural aberrations in lung morphology following 7-day continuous in vivo hyperoxia exposure to neonatal rats. We also tested whether treatment of neonatal pups with RGZ, concomitant to hyperoxia, could prevent such aberrations. Our study revealed that hyperoxia caused significant upregulation of Wnt signaling protein markers lymphoid enhancer factor 1 (Lef-1) and β-catenin and TGF-β pathway transducers phosphorylated Smad3 and Smad7 proteins in whole rat lung extracts. These changes were also accompanied by upregulation of myogenic marker proteins α-smooth muscle actin (α-SMA) and calponin but significant downregulation of the lipogenic marker peroxisome proliferator-activated receptor-γ (PPARγ) expression. These molecular perturbations were associated with reduction in alveolar septal thickness, radial alveolar count, and larger alveoli in the hyperoxia-exposed lung. These hyperoxia-induced molecular and morphological changes were prevented by systemic administration of RGZ, with lung sections appearing near normal. This is the first evidence that in vivo hyperoxia induces activation of both Wnt and TGF-β signal transduction pathways in lung and of its near complete prevention by RGZ. Hyperoxia-induced arrest in alveolar development, a hallmark of BPD, along with these molecular changes strongly implicates these proteins in hyperoxia-induced lung injury. Administration of PPARγ agonists may thus be a potential strategy to attenuate hyperoxia-induced lung injury and subsequent BPD.

scholarly journals Effects of Pirfenidone and Nintedanib on Markers of Systemic Oxidative Stress and Inflammation in Patients with Idiopathic Pulmonary Fibrosis: A Preliminary Report

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1064
Author(s):  
Alessandro G. Fois ◽  
Elisabetta Sotgiu ◽  
Valentina Scano ◽  
Silvia Negri ◽  
Sabrina Mellino ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Thiobarbituric Acid ◽  
Related Factor ◽  
Beneficial Effects ◽  
Systemic Oxidative Stress ◽  
Markers Of Oxidative Stress

Introduction: In vitro evidence suggests that pirfenidone and nintedanib, approved agents for the treatment of idiopathic pulmonary fibrosis (IPF), exert anti-inflammatory and anti-oxidant effects. We aimed to investigate such effects in vivo in IPF patients. Methods: Systemic circulating markers of oxidative stress [nuclear factor erythroid 2–related factor 2 (Nrf2), thiobarbituric acid- reactive substances (TBARS), homocysteine (Hcy), cysteine (Cys), asymmetric dimethylarginine (ADMA) and ADMA/Arginine ratio, glutathione (GSH), plasma protein –SH (PSH), and taurine (Tau)] and inflammation [Kynurenine (Kyn), Tryptophan (Trp) and Kyn/Trp ratio] were measured at baseline and after 24-week treatment in 18 IPF patients (10 treated with pirfenidone and 8 with nintedanib) and in 18 age- and sex-matched healthy controls. Results: Compared to controls, IPF patients had significantly lower concentrations of reduced blood GSH (457 ± 73 µmol/L vs 880 ± 212 µmol/L, p < 0.001) and plasma PSH (4.24 ± 0.95 µmol/g prot vs 5.28 ± 1.35 µmol/g prot, p = 0.012). Pirfenidone treatment significantly decreased the Kyn/Trp ratio (0.030 ± 0.011 baseline vs 0.025 ± 0.010 post-treatment, p = 0.048) whilst nintedanib treatment significantly increased blood GSH (486 ± 70 μmol/L vs 723 ± 194 μmol/L, p = 0.006) and reduced ADMA concentrations (0.501 ± 0.094 vs. 0.468 ± 0.071 μmol/L, p = 0.024). Conclusion: pirfenidone and nintedanib exert beneficial effects on specific markers of oxidative stress and inflammation in IPF patients.

Pathogenesis pathways of idiopathic pulmonary fibrosis in bleomycin-induced lung injury model in mice

2014 ◽  
Vol 190 ◽  
pp. 113-117 ◽  
Author(s):  
Keyun Shi ◽  
Jianzhong Jiang ◽  
Tieliang Ma ◽  
Jing Xie ◽  
Lirong Duan ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Injury Model ◽  
Lung Injury Model

scholarly journals Thymosin β4-Enhancing Therapeutic Efficacy of Human Adipose-Derived Stem Cells in Mouse Ischemic Hindlimb Model

2020 ◽  
Vol 21 (6) ◽  
pp. 2166
Author(s):  
Jong-Ho Kim ◽  
I-Rang Lim ◽  
Chi-Yeon Park ◽  
Hyung Joon Joo ◽  
Ji-Min Noh ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intracellular Signaling ◽  
Morphological Changes ◽  
Additional Treatment ◽  
Endothelial Differentiation ◽  
Adipose Derived Stem Cells ◽  
Thymosin Β4 ◽  
Differentiation Potential ◽  
Beneficial Effects

Thymosin β4 (Tβ4) is a G-actin sequestering protein that contributes to diverse cellular activities, such as migration and angiogenesis. In this study, the beneficial effects of combined cell therapy with Tβ4 and human adipose-derived stem cells (hASCs) in a mouse ischemic hindlimb model were investigated. We observed that exogenous treatment with Tβ4 enhanced endogenous TMSB4X mRNA expression and promoted morphological changes (increased cell length) in hASCs. Interestingly, Tβ4 induced the active state of hASCs by up-regulating intracellular signaling pathways including the PI3K/AKT/mTOR and MAPK/ERK pathways. Treatment with Tβ4 significantly increased cell migration and sprouting from microbeads. Moreover, additional treatment with Tβ4 promoted the endothelial differentiation potential of hASCs by up-regulating various angiogenic genes. To evaluate the in vivo effects of the Tβ4-hASCs combination on vessel recruitment, dorsal window chambers were transplanted, and the co-treated mice were found to have a significantly increased number of microvessel branches. Transplantation of hASCs in combination with Tβ4 was found to improve blood flow and attenuate limb or foot loss post-ischemia compared to transplantation with hASCs alone. Taken together, the therapeutic application of hASCs combined with Tβ4 could be effective in enhancing endothelial differentiation and vascularization for treating hindlimb ischemia.

scholarly journals Eurycomanone regulates lipid metabolism by activating the cAMP/PKA pathway

2020 ◽  
Author(s):  
Zhihui Jiang ◽  
Haote Han ◽  
Shouxin Li ◽  
Jingkui Tian ◽  
Zhiyuan Gao ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Hormone Sensitive Lipase ◽  
Intragastric Administration ◽  
High Fat ◽  
Pharmacologic Agent ◽  
Promising Alternative ◽  
Beneficial Effects ◽  
Eurycoma Longifolia ◽  
Pka Pathway

AbstractEurycoma longifolia Jack (ELJ) contains mainly alkaloids, and quassinoids, which are the main active ingredients. Eurycomanone (EN), one of the most common quassinoids, is said to have beneficial effects on lipid and glucose metabolism. In this study, we investigated the effects of EN on lipolysis by establishing a high-fat animal model in vivo and evaluated its efficacy as a lipolytic and anti-fatty liver agent. Oil red O staining showed morphological changes of 3T3-L1 preadipocytes after EN treatment and confirmed the inhibitory effects of EN on adipocyte differentiation. The mechanism of EN promotes lipolysis in 3T3-L1 cells was analyzed by immunofluorescence, Western blotting, quantitative real-time PCR and siRNA transfection. In C57BL/6J mice fed a high-fat diet, intragastric administration of EN (5 mg/kg and 10 mg/kg) for two weeks, decreased fat droplet mass and size, and reduced fat accumulation in the liver. Furthermore, EN activated PKA and promoted the PKA/hormone sensitive lipase lipolysis signaling pathway, thereby increasing the release of glycerol and free fatty acids from adipocytes. Our findings indicate the potential of EN as a promising alternative pharmacologic agent for the prevention of obesity.

Inhibition of PARS attenuates endotoxin-induced dysfunction of pulmonary vasorelaxation

1999 ◽  
Vol 277 (4) ◽  
pp. L769-L776 ◽  
Author(s):  
Edward J. Pulido ◽  
Brian D. Shames ◽  
Craig H. Selzman ◽  
Hazel A. Barton ◽  
Anirban Banerjee ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Vascular Dysfunction ◽  
Calcium Ionophore ◽  
Structural Analog ◽  
Myeloperoxidase Activity ◽  
Response Curves ◽  
Beneficial Effects ◽  
Pulmonary Arterial

Endotoxin (Etx) causes excessive activation of the nuclear repair enzyme poly(ADP-ribose) synthase (PARS), which depletes cellular energy stores and leads to vascular dysfunction. We hypothesized that PARS inhibition would attenuate injury to mechanisms of pulmonary vasorelaxation in acute lung injury. The purpose of this study was to determine the effect of in vivo PARS inhibition on Etx-induced dysfunction of pulmonary vasorelaxation. Rats received intraperitoneal saline or Etx ( Salmonella typhimurium; 20 mg/kg) and one of the PARS inhibitors, 3-aminobenzamide (3-AB; 10 mg/kg) or nicotinamide (Nic; 200 mg/kg), 90 min later. After 6 h, concentration-response curves were determined in isolated pulmonary arterial rings. Etx impaired endothelium-dependent (response to ACh and calcium ionophore) and -independent (sodium nitroprusside) cGMP-mediated vasorelaxation. 3-AB and Nic attenuated Etx-induced impairment of endothelium-dependent and -independent pulmonary vasorelaxation. 3-AB and Nic had no effect on Etx-induced increases in lung myeloperoxidase activity and edema. Lung ATP decreased after Etx but was maintained by 3-AB and Nic. Pulmonary arterial PARS activity increased fivefold after Etx, which 3-AB and Nic prevented. The beneficial effects were not observed with benzoic acid, a structural analog of 3-AB that does not inhibit PARS. Our results suggest that PARS inhibition with 3-AB or Nic improves pulmonary vasorelaxation and preserves lung ATP levels in acute lung injury.

scholarly journals DNaseI Protects against Paraquat-Induced Acute Lung Injury and Pulmonary Fibrosis Mediated by Mitochondrial DNA

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Guo Li ◽  
Li Yuzhen ◽  
Chen Yi ◽  
Chen Xiaoxiang ◽  
Zhou Wei ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Alveolar Epithelial Cell ◽  
Disease Model ◽  
Lavage Fluid ◽  
Alveolar Epithelial ◽  
Fast Tracking ◽  
Lung Injury Model

Background. Paraquat (PQ) poisoning is a lethal toxicological challenge that served as a disease model of acute lung injury and pulmonary fibrosis, but the mechanism is undetermined and no effective treatment has been discovered.Methods and Findings. We demonstrated that PQ injures mitochondria and leads to mtDNA release. The mtDNA mediated PBMC recruitment and stimulated the alveolar epithelial cell production of TGF-β1 in vitro. The levels of mtDNA in circulation and bronchial alveolar lavage fluid (BALF) were elevated in a mouse of PQ-induced lung injury. DNaseI could protect PQ-induced lung injury and significantly improved survival. Acute lung injury markers, such as TNFα, IL-1β, and IL-6, and marker of fibrosis, collagen I, were downregulated in parallel with the elimination of mtDNA by DNaseI. These data indicate a possible mechanism for PQ-induced, mtDNA-mediated lung injury, which may be shared by other causes of lung injury, as suggested by the same protective effect of DNaseI in bleomycin-induced lung injury model. Interestingly, increased mtDNA in the BALF of patients with amyopathic dermatomyositis-interstitial lung disease can be appreciated.Conclusions. DNaseI targeting mtDNA may be a promising approach for the treatment of PQ-induced acute lung injury and pulmonary fibrosis that merits fast tracking through clinical trials.

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