Vol 77, No 3 (2018)
Original article
Published online: 2017-12-28
Vascular endothelial growth factor receptor inhibition enhances chronic obstructive pulmonary disease picture in mice exposed to waterpipe smoke
Abstract
Background: Chronic obstructive pulmonary disease (COPD) is marked by destruction of alveolar architecture. Preclinical modelling for COPD is challenging. Chronic cigarette smoke exposure, the reference animal model of COPD, is time-inefficient, while exposure to waterpipe smoke (WPS), a surging smoking modality, was not fully tested for its histopathological pulmonary consequences. Since alveolar damage and pulmonary vascular endothelial dysfunction are integral to COPD pathology, lung histopathological effects of WPS were temporally evaluated, alone or in combination with vascular endothelial growth factor receptor (VEGFR) inhibition in mice.
Materials and methods: Mice were exposed to WPS, 3 hours/day, 5 days/week, for 1, 2, 3, or 4 months. Another group of mice was exposed to WPS for 1 month, while being subjected to injections with the VEGFR blocker Sugen5416 (SU, 20 mg/kg) 3 times weekly. Control mice were exposed to fresh air in a matching inhalation chamber. Histopathological assessment of COPD was performed. Alveolar destructive index (DI) was counted as the percentage of abnormally enlarged alveoli with damaged septa per all alveoli counted. Mean linear intercept (MLI) was calculated as a measure of airspace enlargement.
Results: Exposure to WPS resulted in significant increases in alveolar DI and MLI only after 4 months. Lung inflammatory score was minimal across all time-points. Importantly, combination of WPS and SU resulted in significantly increased DI, MLI, and inflammatory scores as early as 1 month post exposure.
Conclusions: Combined exposure to WPS and SU results in COPD picture, highlighting the role of pulmonary vascular endothelial dysfunction in the disease.
Keywords: vascular endothelial growth factor receptorwaterpipe smokechronic obstructive pulmonary diseaseSugen5416
References
- Adeloye D, Chua S, Lee C, et al. Global Health Epidemiology Reference Group (GHERG). Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J Glob Health. 2015; 5(2): 020415.
- Alzoubi A, Toba M, Abe K, et al. Dehydroepiandrosterone restores right ventricular structure and function in rats with severe pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol. 2013; 304(12): H1708–H1718.
- Barberà JA, Peinado VI, Santos S. Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Resp J. 2003; 21(5): 892–905.
- Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med. 2000; 343(4): 269–280.
- Barr RG, Mesia-Vela S, Austin JHM, et al. Impaired flow-mediated dilation is associated with low pulmonary function and emphysema in ex-smokers: the Emphysema and Cancer Action Project (EMCAP) Study. Am J Respir Crit Care Med. 2007; 176(12): 1200–1207.
- Bartalesi B, Cavarra E, Fineschi S, et al. Different lung responses to cigarette smoke in two strains of mice sensitive to oxidants. Eur Respir J. 2005; 25(1): 15–22.
- Beasley R, Weatherall M, Travers J, et al. Time to define the disorders of the syndrome of COPD. Lancet. 2009; 374(9691): 670–672.
- Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med. 2008; 178(4): 332–338.
- Celli BR, Decramer M, Wedzicha JA, et al. An Official American Thoracic Society/European Respiratory Society Statement: Research questions in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015; 191(7): e4–ee27.
- Churg A, Cosio M, Wright JL. Mechanisms of cigarette smoke-induced COPD: insights from animal models. Am J Physiol Lung Cell Mol Physiol. 2008; 294(4): L612–L631.
- Ciuclan L, Bonneau O, Hussey M, et al. A novel murine model of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2011; 184(10): 1171–1182.
- Cobb CO, Shihadeh A, Weaver MF, et al. Waterpipe tobacco smoking and cigarette smoking: a direct comparison of toxicant exposure and subjective effects. Nicotine Tob Res. 2011; 13(2): 78–87.
- Dinh-Xuan AT, Higenbottam TW, Clelland CA, et al. Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med. 1991; 324(22): 1539–1547.
- El-Zaatari ZM, Chami HA, Zaatari GS. Health effects associated with waterpipe smoking. Tob Control. 2015; 24 Suppl 1: i31–i43.
- Fabbri LM, Hurd SS. Global Strategy for the Diagnosis, Management and Prevention of COPD: 2003 update. Eur Respir J. 2003; 22(1): 1–2.
- GoCo R, Kress M, Brantigan O. Comparison of mucus glands in the tracheobronchial tree of man and animals*. Ann N Y Acad Sci. 2008; 106(2): 555–571.
- Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004; 364(9435): 709–721.
- Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004; 350(26): 2645–2653.
- Kasahara Y, Tuder RM, Taraseviciene-Stewart L, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest. 2000; 106(11): 1311–1319.
- Kasahara Y, Tuder RM, Cool CD, et al. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med. 2001; 163(3 Pt 1): 737–744.
- Katurji M, Daher N, Sheheitli H, et al. Direct measurement of toxicants inhaled by water pipe users in the natural environment using a real-time in situ sampling technique. Inhal Toxicol. 2010; 22(13): 1101–1109.
- Khabour OF, Alzoubi KH, Bani-Ahmad M, et al. Acute exposure to waterpipe tobacco smoke induces changes in the oxidative and inflammatory markers in mouse lung. Inhal Toxicol. 2012; 24(10): 667–675.
- Kheirallah KA, Alsulaiman JW, Mohammad H AS, et al. Waterpipe Tobacco Smoking among Arab Youth; a Cross-Country Study. Ethn Dis. 2016; 26(1): 107–112.
- Komurcuoglu A, Kalenci S, Kalenci D. Microalbuminuria in chronic obstructive pulmonary disease. Monaldi Arch Chest Dis. 2003; 59(4): 269–272.
- Macleod LJ, Heard BE. Area of muscle in tracheal sections in chronic bronchitis, measured by point-counting. J Pathol. 1969; 97(1): 157–161.
- Marwick JA, Stevenson CS, Giddings J, et al. Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition. Am J Physiol Lung Cell Mol Physiol. 2006; 290(5): L897–L908.
- Maziak W, Rastam S, Ibrahim I, et al. CO exposure, puff topography, and subjective effects in waterpipe tobacco smokers. Nicotine Tob Res. 2009; 11(7): 806–811.
- Maziak W. The global epidemic of waterpipe smoking. Addict Behav. 2011; 36(1-2): 1–5.
- Maziak W. The waterpipe: a new way of hooking youth on tobacco. Am J Addict. 2014; 23(2): 103–107.
- Maziak W, Taleb ZB, Bahelah R, et al. The global epidemiology of waterpipe smoking. Tob Control. 2015; 24 Suppl 1: i3–ii12.
- Otsuki S, Sawada H, Yodoya N, et al. Potential contribution of phenotypically modulated smooth muscle cells and related inflammation in the development of experimental obstructive pulmonary vasculopathy in rats. PLoS One. 2015; 10(2): e0118655.
- Peinado VI, Barbera JA, Ramirez J, et al. Endothelial dysfunction in pulmonary arteries of patients with mild COPD. Am J Physiol. 1998; 274(6 Pt 1): L908–L913.
- Polatli M, Cakir A, Cildag O, et al. Microalbuminuria, von Willebrand factor and fibrinogen levels as markers of the severity in COPD exacerbation. J Thromb Thrombolysis. 2008; 26(2): 97–102.
- Primack BA, Carroll MV, Weiss PM, et al. Systematic review and meta-analysis of inhaled toxicants from waterpipe and cigarette smoking. Public Health Rep. 2016; 131(1): 76–85.
- Robbesom AA, Versteeg EMM, Veerkamp JH, et al. Morphological quantification of emphysema in small human lung specimens: comparison of methods and relation with clinical data. Mod Pathol. 2003; 16(1): 1–7.
- Rosenberg SR, Kalhan R, Mannino DM. Epidemiology of chronic obstructive pulmonary disease: prevalence, morbidity, mortality, and risk factors. Semin Respir Crit Care Med. 2015; 36(4): 457–469.
- Saetta M, Shiner RJ, Angus GE, et al. Destructive index: a measurement of lung parenchymal destruction in smokers. Am Rev Respir Dis. 1985; 131(5): 764–769.
- Santos S, Peinado VI, Ramirez J, et al. Enhanced expression of vascular endothelial growth factor in pulmonary arteries of smokers and patients with moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003; 167(9): 1250–1256.
- Shihadeh A, Azar S, Antonios C, et al. Towards a topographical model of narghile water-pipe café smoking: a pilot study in a high socioeconomic status neighborhood of Beirut, Lebanon. Pharmacol Biochem Behav. 2004; 79(1): 75–82.
- Singh S, Soumya M, Saini A, et al. Breath carbon monoxide levels in different forms of smoking. Indian J Chest Dis Allied Sci. 2011; 53(1): 25–28.
- Stacher E, Graham BB, Hunt JM, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012; 186(3): 261–272.
- Toba M, Alzoubi A, O'Neill KD, et al. Temporal hemodynamic and histological progression in Sugen5416/hypoxia/normoxia-exposed pulmonary arterial hypertensive rats. Am J Physiol Heart Circ Physiol. 2014; 306(2): H243–H250.
- Voelkel N, Cool C, Taraceviene-Stewart L, et al. Janus face of vascular endothelial growth factor: The obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension. Crit Care Med. 2002; 30(5 Suppl): S251–S256.
- Voelkel NF, Vandivier RW, Tuder RM. Vascular endothelial growth factor in the lung. Am J Physiol Lung Cell Mol Physiol. 2006; 290(2): L209–L221.
- Wright JL, Churg A. Animal models of COPD: Barriers, successes, and challenges. Pulm Pharmacol Ther. 2008; 21(5): 696–698.
- Wright JL, Cosio M, Churg A. Animal models of chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2008; 295(1): L1–15.
