BackgroundProteases may play an important role in the development of chronic obstructive pulmonary disease and emphysema in response to cigarette smoke exposure (CSE). The current study was designed to investigate the expression of matrix metalloproteinase (MMP)-8, MMP-9, MMP-12, tissue inhibitor of MMP (TIMP)-1, and TIMP-4 in rat lung tissues in response to CSE, and assessed the effect of simvastatin in regulating expression of MMPs and TIMPs.MethodsThirty normal Sprague Dawley (SD) rats were divided into control (n=10), CSE (n=10), and CSE plus simvastatin (n=10) groups. Animals were whole-body exposed to the cigarette smoke in the box for 1 hour each time, twice a day, 5 days a week for 16 weeks. Animals of CSE + simvastatin group were intra-gastrically administered simvastatin at a dose of 5 mg/kg/day followed by CSE. Bronchoalveolar lavage fluid was harvested for inflammatory cell count and lung tissues were stained for morphologic examination. Expression of mRNA and protein level of MMP-8, MMP-9, MMP-12, TIMP-1, and TIMP-4 was assessed by real-time reverse transcription polymerase chain reaction and immunohistochemistry, respectively.ResultsCSE resulted in a significant increase of mean linear intercept (MLI: 34.6±2.0 μm) and bronchial wall thickness and diameter (BWT/D, 0.250±0.062) compared to control (MLI: 24.0±1.7 μm, BWT/D: 0.160±0.034, P<0.01). In contrast, mean alveolar number was significantly decreased in the CSE group than that in the control group (13.5±2.0 of CSE vs 21.5±2.0 N/μm2 of control, P>0.01). Simvastatin slightly but not significantly prevented alteration of MLI, BWT/D, and mean alveolar number (MLI: 33.4±1.4 μm; BWT/D: 0.220±0.052; mean alveolar number: 15.5±2.5 N/μm2, P>0.05). Total white blood cell was significantly increased in the bronchoalveolar lavage fluid of smoking group (3.3±2.5×109 cells/L vs 1.1±1.3×109 cells/L of control, P<0.01), and it was significantly reduced by simvastatin (2.3±2.1×109 cells/L, P<0.01). CSE resulted in significantly increased accumulation of neutrophils and macrophages (neutrophils: 14.5%±1.3% of CSE group vs 9.1%±1.5% of control; macrophage: 91%±3% of CSE group vs 87%±2% of control, P<0.05), and simvastatin significantly reduced neutrophils (12.9%±2.0%, P<0.05) in the bronchoalveolar lavage fluid, but had no effect on macrophage (89%±1.6%, P>0.05). In response to CSE, MMP-8, MMP-9, and MMP-12 mRNA were upregulated more than sevenfold, while TIMP-1 and TIMP-4 increased two- to fivefold. Simvastatin significantly blocked upregulation of MMP-8 and -9 (P<0.01), but had no effect on MMP-12, TIMP-1 and TIMP-4 mRNA (P>0.05). In addition, simvastatin significantly blocked cigarette smoke-induced MMP-8 and -9 protein synthesis, while it had no significant effect on TIMP-1 and -4 protein synthesis even in the presence of cigarette smoke.ConclusionCSE resulted in imbalance of MMPs and TIMPs, and by which mechanism, cigarette smoke may lead to insufficient lung tissue repair. Simvastatin partially blocked airway inflammation and MMP production and, thus, statins...
Background/Aims: To investigaterole of serotonin (5-HT) and serotonin transporter (5-HTT) in a rat model of cigarette smoke-induced pulmonary artery hypertension (PAH) and the effect of statins on regulating 5HT and 5-HTT. Methods: A rat model of COPD comorbid with PAH was established by cigarette smoke exposure with or without simvastatin administration. The smoking and the simvastatin plus smoking groups were exposed to cigarette smoke daily, and the latter received simvastatin at 5mg/kg, once a day. After 16 weeks of cigarette smoke exposure, body weight and mean pulmonary arterial pressure (mPAP) were measured, bronchoalveolar lavage (BAL) was performed, and lung tissues and blood samples were collected to determine cardiopulmonary pathology, physiological indices, blood levelof 5-HT and expression of 5-HTT in the lung. Results: In addition to alveolar structural damage (COPD-like injury), chronic cigarette smoke exposure lead to pulmonary artery remodeling and PAH as evidenced by significant elevation of mPAP, RVHI, WT%and WA%. Cigarette smoke exposure resulted in significant reduction in animal body weight, and simvastatin significantly prevented smoke-induced weight loss. The number of inflammatory cells in BALF was dramatically increased in smoke exposed rats, and simvastatin dampened the number of leukocytes, neutrophils, lymphocytes, and macrophages. In addition, circulating 5-HTand expression of 5-HTT in the lung were significantly increased in the smoked rats compared to control rats, and it was significantly reduced by simvastatin. Alteration of BALF inflammatory cells, 5-HT and 5-HTT was significantly correlated with changes of mPAP, RVHI, WT% and WA%. Conclusions: Cigarette smoke exposure could result in not only COPD, but also PAH, which may attribute to the alteration of blood 5-HT and lung tissue 5-HTT. Simvastatin could significantly inhibited 5-HT and 5-HTT expression, and by which mechanism, it may protect animals from development of PAH.
To study the relationship between neutrophil to lymphocyte ratio (NLR) and exercise tolerance of patients with chronic obstructive pulmonary disease (COPD). 235 patients with COPD were selected as the study subjects. Complete blood count, C reactive protein (CRP), pulmonary function tests, the 6-minute walk distance (6MWD), Modified Medical Respiratory Council, the COPD assessment test, and clinical COPD questionnaire were tested. Heart rate, oxygen saturation, and Borg scale were tested before or after 6MWD test. By the median of NLR, the subjects were divided into 2 groups, NLR ≥4.5 group and NLR <4.5 group. The white blood cell count (WBC), CRP and deoxygenation saturation in the NLR ≥4.5 group were higher than those in the NLR <4.5 group, while the age, body mass index (BMI), 6MWD, and heart rate variation were lower than those in the NLR <4.5 group. CRP, WBC, and deoxygenation saturation had positive effects on NLR, BMI, 6MWT, and heart rate variation had negative effects on NLR. The Pearson correlation analysis showed NLR was positively correlated with WBC, CRP, BMI index, 6MWT, and deoxygenation saturation, while it was negatively correlated with BMI and heart rate variation. NLR might associate with exercise tolerance and cardiorespiratory reserve of COPD patients, and could be used as an indicator of muscle function in COPD patients.
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