The effect of azithromycin on pulmonary vascular remodeling in chronic obstructive pulmonary disease rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

FAN Mei , DENG Jun ,  WANG Songping

The First Department of Respiratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;

Corresponding author：

WANG Songping, Email: wang4816@sina.com

Keywords：

Azithromycin; Chronic obstructive pulmonary disease; Pulmonary vascular remodeling; Osteopontin

DOI：

10.7507/1671-6205.201710006

Video：

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ObjectiveTo investigate the effect of azithromycin on chronic obstructive pulmonary disease (COPD) vascular remodeling and its possible mechanism.MethodsEighteen male SD rats were randomly divided into normal control group (group A), model group (group B) and azithromycin intervention group (group C). In group B and group C, the COPD model was established by passive smoking and intratracheal injection of lipopolysaccharide. On the fifteenth day, group C was intragastricly administrated with azithromycin (50 mg/kg) one hour prior to smoking, while group A and group B were given equal amount of normal saline. All the rats were killed 6 weeks later. Hematoxylin-eosin staining was used to observe lung tissue pathological changes and victoria blue + Van Gieson staining was used to observe the pulmonary artery morphology changes. The serum osteopontin (OPN) was determined with ELISA. The protein expression of OPN was measured with immunohistochemistry and OPN mRNA was detected by RT-PCR.ResultsCompared with group A, the degree of pulmonary vascular inflammation and pulmonary vascular remodeling in groups B and C was more serious, but these changes in group C were lighter than those in group B. The serum OPN content, lung tissue OPN protein and OPN mRNA expression in groups B and C were higher than those in group A, while these parameters in group C were lower than those in group B. The content of serum OPN, the expression of OPN protein and OPN mRNA in lung tissue were positively correlated with the degree of pulmonary vascular inflammation and vascular remodeling.ConclusionAzithromycin can alleviate the pulmonary vascular inflammation and pulmonary vascular remodeling in COPD rats, and its mechanism may be related to inhibiting the expression of OPN.

Citation： FAN Mei, DENG Jun, WANG Songping. The effect of azithromycin on pulmonary vascular remodeling in chronic obstructive pulmonary disease rats. Chinese Journal of Respiratory and Critical Care Medicine, 2018, 17(2): 128-133. doi: 10.7507/1671-6205.201710006 Copy

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4.	Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy.Am J Respir Crit Care Med, 2014, 189(12): 1503-1508.
5.	Poachanukoon O, Koontongaew S, Monthanapisut P, et al. Macrolides attenuate phorbolester-induced tumor necrosis factor alpha and mucin production from human airway epithelial cells.Pharmacology, 2014, 93(2): 92-99.
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8.	Miao L, Gao Z, Huang F, et al. Erythromycin enhances the anti-inflammatory activity of budesonide in COPD rat mode. Int J Clin Exp Med, 2015, 8(12): 22217-22226.
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11.	张伟, 谷明明, 孙璐璐, 等. COPD 大鼠肺血管重构与气管重塑的实验研究. 安徽医科大学学报, 2013, 48 (3): 245-248.
12.	Ramos FL, Criner GJ. Use of long-term macrolide therapy in chronic obstructive pulmonary disease. Curr Opin Pulm Med, 2014, 20(2): 153-158.
13.	Porter JD, Watson J, Roberts LR, et al. Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium. J Antimicrob Chemother, 2016, 79(10): 2767-2781.
14.	Arfè A, Blasi F, Merlino L. Respiratory drugs and macrolides prevent asthma exacerbations: A real-world investigation. Respir Med, 2016, 119: 7-12.
15.	郭彩霞. 阿奇霉素经 TLR-4/NF-κB 信号通路干预 COPD 大鼠炎症的机制研究. 重庆医学, 2016, 45(12): 1612-1615.
16.	Hodge S, Hodge G, Holmes M, et al. Increased CD8 T-cell granzyme B in COPD is suppressed by treatment with low-dose azithromycin. Respirology, 2015, 20(1): 95-100.
17.	Rosenberg M, Meyer FJ, Gruenig E, et al. Osteopontin (OPN) improves risk stratification in pulmonary hypertension (PH). Int J Cardiol, 2012, 155(3): 504-505.
18.	Anwar A, Li M, Frid MG, et al. Osteopontin is an endogenous modulator of the constitutively activated phenotype of pulmonary adventitial fibroblasts in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol, 2012, 303(1): L1-L11.
19.	Liu J, Liu Q, Wan Y, et al. Osteopontin promotes the progression of gastric cancer through the NF-kappaB pathway regulated by the MAPK and PI3K. Int J Oncoll, 2014, 45(1): 282-90.
20.	Seo KW, Lee SJ, Ye BH, et al. Mechanical stretch enhances the expression and activity of osteopontin and MMP-2 via the Akt1/AP-1 pathways in VSMC. J Mol Cell Cardiol, 2015, 85: 13-24.

1. Global initiative for chronic obstructive lung disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease 2017 report[EB/OL]. http://www.goldcopd.org.
2. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD.N Engl J Med, 2011, 365(8): 689-698.
3. Uzun S, Djamin RS, Kluytmans JA, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial.Lancet Respir Med, 2014, 2(5): 361-368.
4. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy.Am J Respir Crit Care Med, 2014, 189(12): 1503-1508.
5. Poachanukoon O, Koontongaew S, Monthanapisut P, et al. Macrolides attenuate phorbolester-induced tumor necrosis factor alpha and mucin production from human airway epithelial cells.Pharmacology, 2014, 93(2): 92-99.
6. Cramer CL, Patterson A, Alchakaki A. Immunomodulatory indications of azithromycin in respiratory disease: a concise review for the clinician.Postgrad Med, 2017, 129(5): 493-499.
7. Willems-Widyastuti A, Vanaudenaerde BM, Vos R, et al. Azithromycin attenuates fibroblast growth factors induced vascular endothelial growth factor via p38(MAPK) signaling in human airway smooth muscle cells. Cell Biochem Biophys, 2013, 67(2): 331-339.
8. Miao L, Gao Z, Huang F, et al. Erythromycin enhances the anti-inflammatory activity of budesonide in COPD rat mode. Int J Clin Exp Med, 2015, 8(12): 22217-22226.
9. Wang Z. Pulmonary vascular mechanics: important contributors to the increased right ventricular afterload of pulmonary hypertension. Exp Physiol, 2013, 98(8): 1267-1273.
10. Sakao S, Voelkel NF. The vascular bed in COPD: pulmonary hypertension and pulmonary vascular alterations. Eur Respir Rev, 2014, 23(133): 350-355.
11. 张伟, 谷明明, 孙璐璐, 等. COPD 大鼠肺血管重构与气管重塑的实验研究. 安徽医科大学学报, 2013, 48 (3): 245-248.
12. Ramos FL, Criner GJ. Use of long-term macrolide therapy in chronic obstructive pulmonary disease. Curr Opin Pulm Med, 2014, 20(2): 153-158.
13. Porter JD, Watson J, Roberts LR, et al. Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium. J Antimicrob Chemother, 2016, 79(10): 2767-2781.
14. Arfè A, Blasi F, Merlino L. Respiratory drugs and macrolides prevent asthma exacerbations: A real-world investigation. Respir Med, 2016, 119: 7-12.
15. 郭彩霞. 阿奇霉素经 TLR-4/NF-κB 信号通路干预 COPD 大鼠炎症的机制研究. 重庆医学, 2016, 45(12): 1612-1615.
16. Hodge S, Hodge G, Holmes M, et al. Increased CD8 T-cell granzyme B in COPD is suppressed by treatment with low-dose azithromycin. Respirology, 2015, 20(1): 95-100.
17. Rosenberg M, Meyer FJ, Gruenig E, et al. Osteopontin (OPN) improves risk stratification in pulmonary hypertension (PH). Int J Cardiol, 2012, 155(3): 504-505.
18. Anwar A, Li M, Frid MG, et al. Osteopontin is an endogenous modulator of the constitutively activated phenotype of pulmonary adventitial fibroblasts in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol, 2012, 303(1): L1-L11.
19. Liu J, Liu Q, Wan Y, et al. Osteopontin promotes the progression of gastric cancer through the NF-kappaB pathway regulated by the MAPK and PI3K. Int J Oncoll, 2014, 45(1): 282-90.
20. Seo KW, Lee SJ, Ye BH, et al. Mechanical stretch enhances the expression and activity of osteopontin and MMP-2 via the Akt1/AP-1 pathways in VSMC. J Mol Cell Cardiol, 2015, 85: 13-24.

Chinese Journal of Respiratory and Critical Care Medicine

The effect of azithromycin on pulmonary vascular remodeling in chronic obstructive pulmonary disease rats

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