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Editorial


BNP has an important role in several other activities in the lung, such as bronchodilatation, pulmonary permeability and surfactant production.35 Therefore, it might be that high circulating levels of BNP released from the heart in states such as HF could have a modulating function on airway smooth muscle (ASM). In effect, BNP relaxes guinea pig tracheal smooth muscle in vitro36


and is effective in preventing ovalbumin-induced


bronchoconstriction and microvascular leakage in guinea pigs in vivo.37 Moreover, recently it has been shown that human recombinant BNP (nesiritide) is a potent bronchodilator in patients with asthma.38


Recently, we documented the relaxant effect of BNP on isolated human bronchi, particularly after passive sensitisation,39


incubation of human bronchial smooth muscle with BNP inhibited constriction induced by cholinergic and histaminergic stimulation.40


and also showed that The


bronchial relaxation induced by BNP appears to be associated with the activation of natriuretic peptide receptor (NPR)1 localised on the bronchial epithelium.40


guanylate cyclase (pGC) domain and this catalyses the formation of cGMP, the downstream second messenger involved in most BNP signalling.41


in vivo and relax ASM in vitro.42


It is well known that agents that activate GCs bronchodilate BNP is able to induce a time- and


concentration-dependent increase of cGMP levels in human ASM cells.43


Although we cannot exclude a role of inflammatory cells based on our results, the removal of the bronchial epithelium completely abolished the bronchial relaxant effects of BNP, suggesting a BNP-related, post-transductional control of bronchial contractility involving bronchial epithelium.40


Intriguingly, bronchial NPR1 immunoreactivity


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2. Taylor DR, Using biomarkers in the assessment of airways disease, J Allergy Clin Immunol, (in press).


3. Cazzola M, Novelli G, Biomarkers in COPD, Pulm Pharmacol Ther, 2010;23(6):493–500.


4. Hunt SA, Abraham WT, Chin MH, et al., 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation, Circulation, 2009;119(14):391–479.


5. Mohammed AA, Januzzi JL Jr, Natriuretic peptides in the diagnosis and management of acute heart failure, Heart Fail Clin, 2009;5(4):489–500.


6. Cowie MR, Struthers AD, Wood DA, et al., Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care, Lancet, 1997;350(9088):1349–53.


7. Januzzi JL Jr, Camargo CA, Anwaruddin S, et al., The N- terminal Pro-BNP Investigation of Dyspnea in the emergency department (PRIDE) study, Am J Cardiol, 2005; 95(8):948–54.


8. Maisel AS, Krishnaswamy P, Nowak RM, et al., Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure, N Engl J Med, 2002;347(3):161–7.


9. Januzzi JL, Jr, van Kimmenade RRJ, Lainchbury JG, et al., NT- proBNP testing for diagnosis and short-term prognosis in acute congestive heart failure: an international pooled analysis of 1256 patients. The International Collaborative of NT-proBNP (ICON) Study, Eur Heart J, 2006;27(3):330–7.


10. Mueller C, Laule-Kilian K, Schindler C, et al., Cost- effectiveness of B-type natriuretic peptide testing in patients with acute dyspnea, Arch Intern Med, 2006;166(10):1081–7.


11. Moe GW, Howlett J, Januzzi JL, et al., N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study, Circulation, 2007;115(24):3103–10.


12. Wang TJ, Larson MG, Levy D, et al., Plasma natriuretic peptide levels and the risk of cardiovascular events and death, N Engl J Med, 2004;350(7):655–63.


13. Yap LB, Mukerjee D, Timms PM, et al., Natriuretic peptides, respiratory disease, and the right heart, Chest, 2004;126(4):1330–6.


14. Ishii J, Nomura M, Ito M, et al., Plasma concentration of brain natriuretic peptide as a biochemical marker for the evaluation


NPR1 contains an intracellular particulate


was detected in epithelium and inflammatory cells, but was faint or absent in ASM cells.40


Methoctramine, an antagonist of M2 muscarinic


receptors, and quinine, an inhibitor of organic cation transporters that reduces acetylcholine (ACh) release, abolished BNP-induced relaxant activity.40


The latter was associated with increased bronchial messenger (m)RNA for nitric oxide synthase (NOS) and NO release, inhibited by L-NAME, a NOS inhibitor, and aminoguanidine, an inhibitor of inducible NOS.40


In vitro, BNP increased ACh release from bronchial epithelial cells, whereas NO release was unchanged.40


Our results suggest that bronchial epithelial cells regulate the BNP-induced relaxant activity in human isolated bronchi by an autocrine loop involving BNP-induced low-dose ACh release from airway epithelium that stimulates NO release from underlying non-epithelial bronchial tissues. We speculate that BNP binding elicits the vesicular release of ACh from bronchial epithelial cells, including neuroendocrine and brush cells. Although there is less ACh released from the airway epithelium compared with that from neurons, it seems to be sufficient to activate postsynaptic M2 muscarinic receptors on the surface of ASM cells, which in turn increases NO and cGMP production.40


These findings support a teleological role for elevated BNP concentrations, at least in patients with COPD, in whom BNP might be part of a response aimed at mitigating the effects of the disease. They add important information to current understanding of the local reciprocal interactions of BNP with bronchial tone control and suggest alternative pharmacological options for chronic airway disease therapy, including bronchial asthma or COPD.44


n


of right ventricular overload and mortality in chronic respiratory disease, Clin Chim Acta, 2000;301(1–2):19–30.


15. Leuchte HH, Neurohr C, Baumgartner R, et al., Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension, Am J Respir Crit Care Med, 2004;170(4):360–5.


16. Yano S, Kobayashi K, Kato K, Ikeda, T, [The study of pulmonary hypertension and plasma BNP values in respiratory diseases], Nihon Kokyuki Gakkai Zasshi, 2006;44(2):99–103.


17. Budweiser S, Luchner A, Jörres RA, et al., NT-proBNP in chronic hypercapnic respiratory failure: a marker of disease severity, treatment effect and prognosis, Respir Med, 2007;101(9):2003–10.


18. Bando M, Ishii Y, Sugiyama Y, Kitamura S, Elevated plasma brain natriuretic peptide levels in chronic respiratory failure with cor pulmonale, Respir Med, 1999;93(7):507–14.


19. Silver MA, Maisel A, Yancy CW, et al., BNP Consensus Panel 2004: a clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular diseases, Congest Heart Fail, 2004;10(5 Suppl. 3):1–30.


20. Bozkanat E, Tozkoparan E, Baysan O, et al., The significance of elevated brain natriuretic peptide levels in chronic obstructive pulmonary disease, J Int Med Res, 2005;33(5):537–44.


21. Inoue Y, Kawayama T, Iwanaga T, Aizawa H, High plasma brain natriuretic peptide levels in stable COPD without pulmonary hypertension or cor pulmonale, Intern Med, 2009;48(11):503–12.


22. Gemici G, Erdim R, Celiker A, et al., B-type natriuretic peptide levels in patients with COPD and normal right ventricular function, Adv Ther, 2008;25(7):674–80.


23. van Gestel YR, Goei D, Hoeks SE, et al., Predictive value of NT-proBNP in vascular surgery patients with COPD and normal left ventricular systolic function, COPD, 2010;7(1):70–5.


24. Gale CP, White JE, Hunter A, et al., Predicting mortality and hospital admission in patients with COPD: significance of NT pro-BNP, clinical and echocardiographic assessment, J Cardiovasc Med (Hagerstown), 2011;12(9):613–8.


25. Stolz D, Breidthardt T, Christ-Crain M, et al., Use of B-type natriuretic peptide in the risk stratification of acute exacerbations of COPD, Chest, 2008;133(5):1088–94.


26. Chang CL, Robinson SC, Mills GD, et al., Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD, Thorax, 2011;66(9):764–8.


27. Medina AM, Marteles MS, Sáiz EB, et al., Prognostic utility of NT-proBNP in acute exacerbations of chronic pulmonary diseases, Eur J Intern Med, 2011;22(2):167–71.


28. Rutten FH, Cramer MJ, Zuithoff NP, et al., Comparison of B-type natriuretic peptide assays for identifying heart failure in stable elderly patients with a clinical diagnosis of chronic obstructive pulmonary disease, Eur J Heart Fail, 2007;9(6–7):651–9.


29. Zhao L, Hughes JM, Winter RJ, Effects of natriuretic peptides and neutral endopeptidase 24.11 inhibition in isolated perfused rat lung, Am Rev Respir Dis, 1992;146(5 pt 1):1198–201.


30. Cargill RI, Lipworth BJ, Acute effects of ANP and BNP on hypoxic pulmonary vasoconstriction in humans, Br J Clin Pharmacol, 1995;40(6):585–90.


31. Cargill RI, Lipworth BJ, Atrial natriuretic peptide and brain natriuretic peptide in cor pulmonale. Hemodynamic and endocrine effects, Chest, 1996;110(5):1220–5.


32. Arjona AA, Hsu CA, Wrenn DS, Hill, NS, Effects of natriuretic peptides on vascular smooth-muscle cells derived from different vascular beds, Gen Pharmacol Vasc Syst, 1997;28(3):387–92


33. Klinger JR, Warburton RR, Pietras L, Hill NS, Brain natriuretic peptide inhibits hypoxic pulmonary hypertension in rats, J Appl Physiol, 1998;84(5):1646–52.


34. Leuchte HH, Michalek J, Soenmez O, et al., Preserved pulmonary vasodilative properties of aerosolized brain natriuretic peptide, Pulm Pharmacol Ther, 2009;22(6):548–53.


35. Hulks G, Jardine AG, Connell JM, Thomson NC, Effect of atrial natriuretic factor on bronchomotor tone in the normal human airway, Clin Sci (Lond), 1990;79(1):51–5.


36. Takagi K, Araki N, Relaxant effects of brain natriuretic peptide on guinea-pig tracheal smooth muscle, Clin Exp Pharmacol Physiol, 1993;20(4):239–43.


37. Ohbayashi H, Suito H, Takagi K, Compared effects of natriuretic peptides on ovalbumin-induced asthmatic model, Eur J Pharmacol, 1998;346(1):55–64.


38. Akerman MJ, Yaegashi M, Khiangte Z, et al., Bronchodilator effect of infused B-type natriuretic peptide in asthma, Chest, 2006;130(1):66–72.


39. Matera MG, Calzetta L, Parascandolo V, et al., Relaxant effect of brain natriuretic peptide in nonsensitized and passively sensitized isolated human bronchi, Pulm Pharmacol Ther, 2009;22(6):478–82.


40. Matera MG, Calzetta L, Passeri D, et al., Epithelium integrity is crucial for the relaxant activity of brain natriuretic peptide in human isolated bronchi, Br J Pharmacol, 2011;163(8):1740–54.


41. Potter LR, Abbey-Hosch S, Dickey DM, Natriuretic peptides, their receptors, and cyclic guanosine monophosphate- dependent signaling functions, Endocr Rev, 2006;27(1):47–72.


42. Hamad AM, Range S, Holland E, Knox AJ, Regulation of cGMP by soluble and particulate guanylyl cyclases in cultured human airway smooth muscle, Am J Physiol, 1997;273(4 pt 1):L807–L13.


43. Hamad AM, Clayton A, Islam B, Knox AJ, Guanylyl cyclases, nitric oxide, natriuretic peptides, and airway smooth muscle function, Am J Physiol Lung Cell Mol Physiol, 2003;285(5):L973–L83.


44. Matera MG, Page CP, Cazzola M, Novel bronchodilators for the treatment of chronic obstructive pulmonary disease, Trends Pharmacol Sci, 2011;32(8):495–506.


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