title: 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.
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.
authors.affiliation: 1. Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan; 2. Department of Medical Research, Mackay Memorial Hospital, Tamsui, Taiwan.
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Hung
authors.affiliation: 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.
authors.forename: Wen-Yeh
authors.initials: WY
authors.lastname: Hsieh
authors.affiliation: 1. Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Jih-Sheng
authors.initials: JS
authors.lastname: Hsieh
authors.affiliation: 1. Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Fon-Chang
authors.initials: FC
authors.lastname: Liu
authors.affiliation: 1. Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Chin-Hung
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: 1. Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan; 5. Division of Nephrology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taiwan.
authors.forename: Li-Che
authors.initials: LC
authors.lastname: Lu
authors.affiliation: 3. Division of Chest Medicine, Department of Internal Medicine, Mackay Memorial Hospital, Hsinchu, Taiwan.
authors.forename: Chen-Yi
authors.initials: CY
authors.lastname: Huang
authors.affiliation: 6. Division of Chest Medicine, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Chien-Liang
authors.initials: CL
authors.lastname: Wu
authors.affiliation: 1. Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Chih-Sheng
authors.initials: CS
authors.lastname: Lin
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D005260:Female; D055370:Lung Injury / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects*
chemical_list: D050796:STAT3 Transcription Factor; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D020782:Matrix Metalloproteinases
keywords: angiotensin converting enzyme II; cigarette smoke; lung injury; matrix metalloproteinases; renin-angiotensin system