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      Alternative Roles of STAT3 and MAPK Signaling Pathways in the MMPs Activation and Progression of Lung Injury Induced by Cigarette Smoke Exposure in ACE2 Knockout Mice

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          Abstract

          Inflammation-mediated abnormalities in the renin-angiotensin system (RAS) and expression of matrix metalloproteinases (MMPs) are implicated in the pathogenesis of lung injury. Angiotensin converting enzyme II (ACE2), an angiotensin converting enzyme (ACE) homologue that displays antagonist effects on ACE/angiotensin II (Ang II) axis, could also play a protective role against lung diseases. However, the relationship between ACE2 and MMPs activation in lung injury is still largely unclear. The purpose of this study is to investigate whether MMPs activity could be affected by ACE2 and which ACE2 derived signaling pathways could be also involved via using a mouse model with lung injury induced by cigarette smoke (CS) exposure for 1 to 3 weeks. Wild-type (WT; C57BL/6) and ACE2 KO mice (ACE2 -/-) were utilized to study CS-induced lung injury. Increases in the resting respiratory rate (RRR), pulmonary immunokines, leukocyte infiltration and bronchial hyperplasia were observed in the CS-exposed mice. Compared to WT mice, more serious physiopathological changes were found in ACE2 -/- mice in the first week of CS exposure. CS exposure increased pulmonary ACE and ACE2 activities in WT mice, and significantly increased ACE in ACE2 -/- mice. Furthermore, the activity of pulmonary MMPs was decreased in CS-exposed WT mice, whereas this activity was increased in ACE2 -/- mice. CS exposure increased the pulmonary p-p38, p-JNK and p-ERK1/2 level in all mice. In ACE2 -/- mice, a significant increase p-STAT3 signaling was detected; however, no effect was observed on the p-STAT3 level in WT mice. Our results support the hypothesis that ACE2 deficiency influences MMPs activation and STAT3 phosphorylation signaling to promote more pulmonary inflammation in the development of lung injury.

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          Most cited references39

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          Mitogen-activated protein kinases in apoptosis regulation.

          Cells are continuously exposed to a variety of environmental stresses and have to decide 'to be or not to be' depending on the types and strength of stress. Among the many signaling pathways that respond to stress, mitogen-activated protein kinase (MAPK) family members are crucial for the maintenance of cells. Three subfamilies of MAPKs have been identified: extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38-MAPKs. It has been originally shown that ERKs are important for cell survival, whereas JNKs and p38-MAPKs were deemed stress responsive and thus involved in apoptosis. However, the regulation of apoptosis by MAPKs is more complex than initially thought and often controversial. In this review, we discuss MAPKs in apoptosis regulation with attention to mouse genetic models and critically point out the multiple roles of MAPKs.
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            The renin-angiotensin system and cancer: old dog, new tricks.

            For cancers to develop, sustain and spread, the appropriation of key homeostatic physiological systems that influence cell growth, migration and death, as well as inflammation and the expansion of vascular networks are required. There is accumulating molecular and in vivo evidence to indicate that the expression and actions of the renin-angiotensin system (RAS) influence malignancy and also predict that RAS inhibitors, which are currently used to treat hypertension and cardiovascular disease, might augment cancer therapies. To appreciate this potential hegemony of the RAS in cancer, an expanded comprehension of the cellular actions of this system is needed, as well as a greater focus on translational and in vivo research.
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              Is Open Access

              Role of TNFα in pulmonary pathophysiology

              Tumor necrosis factor alpha (TNFα) is the most widely studied pleiotropic cytokine of the TNF superfamily. In pathophysiological conditions, generation of TNFα at high levels leads to the development of inflammatory responses that are hallmarks of many diseases. Of the various pulmonary diseases, TNFα is implicated in asthma, chronic bronchitis (CB), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In addition to its underlying role in the inflammatory events, there is increasing evidence for involvement of TNFα in the cytotoxicity. Thus, pharmacological agents that can either suppress the production of TNFα or block its biological actions may have potential therapeutic value against a wide variety of diseases. Despite some immunological side effects, anti-TNFα therapeutic strategies represent an important breakthrough in the treatment of inflammatory diseases and may have a role in pulmonary diseases characterized by inflammation and cell death.
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                Author and article information

                Journal
                Int J Biol Sci
                Int. J. Biol. Sci
                ijbs
                International Journal of Biological Sciences
                Ivyspring International Publisher (Sydney )
                1449-2288
                2016
                12 February 2016
                : 12
                : 4
                : 454-465
                Affiliations
                1. Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
                2. Department of Medical Research, Mackay Memorial Hospital, Tamsui, Taiwan
                3. Division of Chest Medicine, Department of Internal Medicine, Mackay Memorial Hospital, Hsinchu, Taiwan
                4. Department of Senior Citizen Service Management , Minghsin University of Science and Technology, Hsinchu, Taiwan
                5. Division of Nephrology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taiwan
                6. Division of Chest Medicine, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
                Author notes
                ✉ Corresponding author: Chih-Sheng Lin, Ph.D. Department of Biological Science and Technology, National Chiao Tung University, No.75 Po-Ai Street, Hsinchu 30068, Taiwan. Tel.: +886-3-5131338; Fax: +886-3-5729288; E-mail: lincs@ 123456mail.nctu.edu.tw

                † These authors contributed equally to the manuscript.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijbsv12p0454
                10.7150/ijbs.13379
                4807164
                27019629
                ac145adc-30a4-4592-bcd4-9c0073ec9c03
                © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions.
                History
                : 29 July 2015
                : 2 January 2016
                Categories
                Research Paper

                Life sciences
                angiotensin converting enzyme ii,cigarette smoke,lung injury,matrix metalloproteinases,renin-angiotensin system

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