Recombinant Human Keratinocyte Growth Factor Induces Akt Mediated Cell Survival Progression in Emphysematous Mice

Muyal, Jai Prakash; Kumar, Divyesh; Kotnala, Sudhir; Muyal, Vandana; Tyagi, Amit

doi:10.1016/j.arbr.2015.02.023

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…Elastase application in mice is a well‐characterized model of emphysema (Emami et al, 2008; Ishizawa et al, 2004; Lüthje et al, 2009; Munoz‐Barrutia, Ceresa, Artaechevarria, Montuenga, & Ortiz‐de‐Solorzano, 2012; Snider, Lucey, & Stone, 1986; Suki, Bartolak‐Suki, & Rocco, 2017; Valentine, Rucker, Chrisp, & Fisher, 1983) that has successfully been used to study pharmacological preventive (Takahashi et al, 2008; Tanaka et al, 2013) and curative (Padilha et al, 2015; Prakash Muyal, Kumar, Kotnala, Muyal, & Kumar Tyagi, 2015; Yildirim et al, 2010) treatments, yet no study utilizing an iNOS inhibitor in a treatment approach has been published so far. Elastase produces lesions in the lung, resulting in a more severe emphysema, than in the often‐used tobacco smoke model.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of elastase‐induced lung emphysema and reversal of pulmonary hypertension by pharmacological iNOS inhibition in mice

Fysikopoulos

Seimetz

Hadžić

et al. 2020

British J Pharmacology

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Background and Purpose: Chronic obstructive pulmonary disease, encompassing chronic airway obstruction and lung emphysema, is a major worldwide health problem and a severe socio-economic burden. Evidence previously provided by our group has shown that inhibition of inducible NOS (iNOS) prevents development of mild emphysema in a mouse model of chronic tobacco smoke exposure and can even trigger lung regeneration. Moreover, we could demonstrate that pulmonary hypertension is not only abolished in cigarette smoke-exposed iNOS −/− mice but also precedes emphysema development. Possible regenerative effects of pharmacological iNOS inhibition in more severe models of emphysema not dependent on tobacco smoke, however, are hitherto unknown. Experimental Approach:We have established a mouse model using a single dose of porcine pancreatic elastase or saline, intratracheally instilled in C57BL/6J mice.Emphysema, as well as pulmonary hypertension development was determined by both structural and functional measurements.Key Results: Our data revealed that (i) emphysema is fully established after 21 days, with the same degree of emphysema after 21 and 28 days post instillation, (ii) emphysema is stable for at least 12 weeks and (iii) pulmonary hypertension is evident, in contrast to smoke models, only after emphysema development. Oral treatment with the iNOS inhibitor N(6)-(1-iminoethyl)-L-lysine (L-NIL) was started after Abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, global initiative for chronic obstructive lung disease; iNOS, inducible NOS; L-NIL, N(6)-(1-iminoethyl)-L-lysine; LV, left ventricle; MLI, mean linear intercept; ONOO-, peroxynitrite; PBGD, porphobilinogen deaminase; PH, pulmonary hypertension; PPE, porcine pancreatic elastase; RV, right ventricle; RVSP, right ventricular systolic pressure; S, Septum. Athanasios Fysikopoulos, Michael Seimetz, Norbert Weissmann and Simone Kraut have equal contribution.Br J Pharmacol. 2020;1-20.wileyonlinelibrary.com/journal/bph 1 emphysema establishment and continued for 12 weeks. This resulted in significant lung regeneration, evident in the improvement of emphysema and reversal of pulmonary hypertension. Conclusion and Implications:Our data indicate that iNOS is a potential new therapeutic target to treat severe emphysema and associated pulmonary hypertension.

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Section: Discussionmentioning

confidence: 99%

Amelioration of elastase‐induced lung emphysema and reversal of pulmonary hypertension by pharmacological iNOS inhibition in mice

Fysikopoulos

Seimetz

Hadžić

et al. 2020

British J Pharmacology

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“…In the VEGF-mediated signaling pathway, AKT acts as a key regulator, regulating cell survival, proliferation, and angiogenesis ( 36 ). In the lung, the induction of Akt expression have a variety of beneficial effects on cells, especially for the survival of alveolar cells ( 37 ). The reduction of VEGF/VEGFR2 expression can lead to endothelial cell apoptosis, which leads to emphysema changes ( 29 , 38 , 39 ).…”

Section: Discussionmentioning

confidence: 99%

Human Umbilical Cord-Derived Mesenchymal Stem Cells Repair SU5416-Injured Emphysema by Inhibiting Apoptosis via Rescuing VEGF-VEGFR2-AKT Pathway in Rats

Chen

Zheng

et al. 2022

Int J Stem Cells

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Background and Objectives: Chronic obstructive pulmonary disease (COPD) is a common, frequently-occurring disease and poses a major health concern. Unfortunately, there is current no effective treatment for COPD, particularly emphysema. Recently, experimental treatment of COPD using mesenchymal stem cells (MSCs) mainly focused on bone marrow-derived MSCs (BM-MSCs). Human umbilical cord-derived MSCs (hUC-MSCs) have more advantages compared to BM-MSCs. However, studies on the role of hUC-MSCs in management of COPD are limited. This study sought to explore the role of hUC-MSCs and its action mechanisms in a rat model of VEGF receptor blocker SU5416-injured emphysema. Methods and Results: hUC-MSCs were characterized by immunophenotype and differentiation analysis. Rats were divided into four groups: Control, Control＋MSC, SU5416 and SU5416＋MSC. Rats in model group were administered with SU5416 for three weeks. At the end of the second week after SU5416 administration, model group were infused with 3×10 6 hUC-MSCs through tail vein. After 14 days from hUC-MSCs transplantation, rats were euthanized and data were analyzed. HE staining and mean linear intercepts showed that SU5416-treated rats exhibited typical emphysema while emphysematous changes in model rats after hUC-MSCs transplantation disappeared completely and were restored to normal phenotype. Furthermore, hUC-MSCs inhibited apoptosis as shown by TUNEL and Western blotting. ELISA and Western blotting showed hUC-MSCs rescued VEGF-VEGFR2-AKT pathway in emphysematous lungs. Conclusions: The findings show that hUC-MSCs effectively repair the emphysema injury. This study provides the first evidence that hUC-MSCs inhibit apoptosis via rescuing VEGF-VEGFR2-AKT pathway in a rat model of emphysema.

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Macrophage Migration Inhibitory Factor: A Novel Inhibitor of Apoptosis Signal-Regulating Kinase 1–p38–Xanthine Oxidoreductase–Dependent Cigarette Smoke–Induced Apoptosis

Fallica

Varela

Johnston

et al. 2016

Am J Respir Cell Mol Biol

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Cigarette smoke (CS) exposure is the leading cause of emphysema. CS mediates pathologic emphysematous remodeling of the lung via apoptosis of lung parenchymal cells resulting in enlargement of the airspaces, loss of the capillary bed, and diminished surface area for gas exchange. Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, is reduced both in a preclinical model of CS-induced emphysema and in patients with chronic obstructive pulmonary disease, particularly those with the most severe disease and emphysematous phenotype. MIF functions to antagonize CS-induced DNA damage, p53-dependent apoptosis of pulmonary endothelial cells (EndoCs) and resultant emphysematous tissue remodeling. Using primary alveolar EndoCs and a mouse model of CS-induced lung damage, we investigated the capacity and molecular mechanism(s) by which MIF modifies oxidant injury. Here, we demonstrate that both the activity of xanthine oxidoreductase (XOR), a superoxide-generating enzyme obligatory for CS-induced DNA damage and EndoC apoptosis, and superoxide concentrations are increased after CS exposure in the absence of MIF. Both XOR hyperactivation and apoptosis in the absence of MIF occurred via a p38 mitogen-activated protein kinase-dependent mechanism. Furthermore, a mitogen-activated protein kinase kinase kinase family member, apoptosis signal-regulating kinase 1 (ASK1), was necessary for CS-induced p38 activation and EndoC apoptosis. MIF was sufficient to directly suppress ASK1 enzymatic activity. Taken together, MIF suppresses CS-mediated cytotoxicity in the lung, in part by antagonizing ASK1-p38-XOR-dependent apoptosis.

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Recombinant Human Keratinocyte Growth Factor Induces Akt Mediated Cell Survival Progression in Emphysematous Mice

Cited by 3 publications

References 52 publications

Amelioration of elastase‐induced lung emphysema and reversal of pulmonary hypertension by pharmacological iNOS inhibition in mice

Amelioration of elastase‐induced lung emphysema and reversal of pulmonary hypertension by pharmacological iNOS inhibition in mice

Human Umbilical Cord-Derived Mesenchymal Stem Cells Repair SU5416-Injured Emphysema by Inhibiting Apoptosis via Rescuing VEGF-VEGFR2-AKT Pathway in Rats

Macrophage Migration Inhibitory Factor: A Novel Inhibitor of Apoptosis Signal-Regulating Kinase 1–p38–Xanthine Oxidoreductase–Dependent Cigarette Smoke–Induced Apoptosis

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