The online version of this article (doi:10.1186/1465-9921-15-56) contains supplementary material, which is available to authorized users.
Christopher Uhlig, Pedro L Silva contributed equally to this work.
The authors have no competing interests to declare.
This study was financially supported by a personnel exchange grant (PROBRAL) of the Coordination for the Improvement of Higher Education Personnel (CAPES), Brasília, Brazil, and the German Academic Exchange Service (DAAD), Bonn, Germany, as well as educational grants of the Carlos Chagas Filho Rio de Janeiro State Research Foundation (FAPERJ), Rio de Janeiro, Brazil, and the Brazilian Council for Scientific and Technological Development (CNPq), Brasília, Brazil.
CPU participated in the design of the study, carried out the experiments, performed data analyses and drafted the manuscript; PLS contributed to the study design, carried out the experiments, performed data analyses, and wrote the manuscript; DO carried out the molecular biology analyses and contributed to the manuscript; RSS and PJM provided expert assistance during experiments, analyzed mechanical data, and helped draft the manuscript; PMS and TK contributed to the study design and manuscript; MK performed the histological analyses and helped draft the manuscript; BW performed the statistical analyses and helped draft the manuscript; MMM contributed to study design and carried out the molecular biology analyses; PP contributed to the study design, supervised the entire project and helped write the manuscript; MGA and PRMR: contributed to the study design, supervised the experimental work and statistical analysis, wrote the manuscript, supervised the entire project. All authors read and approved the final manuscript.
We investigated the effects of intravenous and intratracheal administration of salbutamol on lung morphology and function, expression of ion channels, aquaporin, and markers of inflammation, apoptosis, and alveolar epithelial/endothelial cell damage in experimental pulmonary (p) and extrapulmonary (exp) mild acute respiratory distress syndrome (ARDS).
In this prospective randomized controlled experimental study, 56 male Wistar rats were randomly assigned to mild ARDS induced by either intratracheal (n = 28, ARDSp) or intraperitoneal (n = 28, ARDSexp) administration of E. coli lipopolysaccharide. Four animals with no lung injury served as controls (NI). After 24 hours, animals were anesthetized, mechanically ventilated in pressure-controlled mode with low tidal volume (6 mL/kg), and randomly assigned to receive salbutamol (SALB) or saline 0.9% (CTRL), intravenously (i.v., 10 μg/kg/h) or intratracheally (bolus, 25 μg). Salbutamol doses were targeted at an increase of ≈ 20% in heart rate. Hemodynamics, lung mechanics, and arterial blood gases were measured before and after (at 30 and 60 min) salbutamol administration. At the end of the experiment, lungs were extracted for analysis of lung histology and molecular biology analysis. Values are expressed as mean ± standard deviation, and fold changes relative to NI, CTRL vs. SALB.
The gene expression of ion channels and aquaporin was increased in mild ARDSp, but not ARDSexp. In ARDSp, intravenous salbutamol resulted in higher gene expression of alveolar epithelial sodium channel (0.20 ± 0.07 vs. 0.68 ± 0.24, p < 0.001), aquaporin-1 (0.44 ± 0.09 vs. 0.96 ± 0.12, p < 0.001) aquaporin-3 (0.31 ± 0.12 vs. 0.93 ± 0.20, p < 0.001), and Na-K-ATPase-α (0.39 ± 0.08 vs. 0.92 ± 0.12, p < 0.001), whereas intratracheal salbutamol increased the gene expression of aquaporin-1 (0.46 ± 0.11 vs. 0.92 ± 0.06, p < 0.001) and Na-K-ATPase-α (0.32 ± 0.07 vs. 0.58 ± 0.15, p < 0.001). In ARDSexp, the gene expression of ion channels and aquaporin was not influenced by salbutamol. Morphological and functional variables and edema formation were not affected by salbutamol in any of the ARDS groups, regardless of the route of administration.
Salbutamol administration increased the expression of alveolar epithelial ion channels and aquaporin in mild ARDSp, but not ARDSexp, with no effects on lung morphology and function or edema formation. These results may contribute to explain the negative effects of β2-agonists on clinical outcome in ARDS.
Additional file 1: This file gives detailed information about extended material and methods used including one table (Table S1 - Polymerase chain reaction (PCR) primers used in the study).(DOCX 34 KB)
Additional file 2: This file contains additional results covering two tables (Table S2 - Body weight, anesthesia and fluid therapy and Table S3 - Ventilator parameters and respiratory mechanics) and one figure (Figure S1 - Wet-to-dry (W/D) ratio).(DOCX 2 MB)
Sakuma T, Suzuki S, Usuda K, Handa M, Okaniwa G, Nakada T, Fujimura S, Matthay MA: Preservation of alveolar epithelial fluid transport mechanisms in rewarmed human lung after severe hypothermia. J Appl Physiol. 1996, 80 (5): 1681-1686. PubMed
McAuley DF, Frank JA, Fang X, Matthay MA: Clinically relevant concentrations of beta2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury. Crit Care Med. 2004, 32 (7): 1470-1476. 10.1097/01.CCM.0000129489.34416.0E. PubMedCrossRef
Frank JA, Wang Y, Osorio O, Matthay MA: Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats. J Appl Physiol. 2000, 89 (4): 1255-1265. PubMed
Gao Smith F, Perkins GD, Gates S, Young D, McAuley DF, Tunnicliffe W, Khan Z, Lamb SE: BALTI-2 study investigators: Effect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet. 2012, 379 (9812): 229-235. 10.1016/S0140-6736(11)61623-1. PubMedCrossRef
Heart N, Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, Holets S, Kallet RH, Liu KD, MacIntyre N, Moss M, Schoenfeld D, Steingrub J, Thompson BT, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: Randomized, placebo-controlled clinical trial of an aerosolized beta(2)-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011, 184 (5): 561-568. CrossRef
Peterson BT, Brooks JA, Zack AG: Use of microwave oven for determination of postmortem water volume of lungs. J Appl Physiol. 1982, 52 (6): 1661-1663. PubMed
Spieth PM, Carvalho AR, Guldner A, Kasper M, Schubert R, Carvalho NC, Beda A, Dassow C, Uhlig S, Koch T, Pelosi P: Pressure support improves oxygenation and lung protection compared to pressure-controlled ventilation and is further improved by random variation of pressure support. Crit Care Med. 2011, 39 (4): 746-755. 10.1097/CCM.0b013e318206bda6. PubMedCrossRef
Rocco PR, Dos Santos C, Pelosi P: Lung parenchyma remodeling in acute respiratory distress syndrome. Minerva Anestesiol. 2009, 75 (12): 730-740. PubMed
He X, Hu JL, Li J, Zhao L, Zhang Y, Zeng YJ, Dai SS, He FT: A feedback loop in PPARgamma-adenosine A2A receptor signaling inhibits inflammation and attenuates lung damages in a mouse model of LPS-induced acute lung injury. Cell Signal. 2013, 25 (9): 1913-1923. 10.1016/j.cellsig.2013.05.024. PubMedCrossRef
Brant KA, Fabisiak JP: Role of hypoxia-inducible factor 1, alpha subunit and cAMP-response element binding protein 1 in synergistic release of interleukin 8 by prostaglandin E2 and nickel in lung fibroblasts. Am J Respir Cell Mol Biol. 2013, 49 (1): 105-113. 10.1165/rcmb.2012-0297OC. PubMedPubMedCentralCrossRef
Dincer HE, Gangopadhyay N, Wang R, Uhal BD: Norepinephrine induces alveolar epithelial apoptosis mediated by alpha-, beta-, and angiotensin receptor activation. Am J Physiol Lung Cell Mol Physiol. 2001, 281 (3): L624-L630. PubMed
Minnear FL, DeMichele MA, Moon DG, Rieder CL, Fenton JW: Isoproterenol reduces thrombin-induced pulmonary endothelial permeability in vitro. Am J Physiol. 1989, 257 (5 Pt 2): H1613-H1623. PubMed
Downs CA, Kriener LH, Yu L, Eaton DC, Jain L, Helms MN: beta-Adrenergic agonists differentially regulate highly selective and nonselective epithelial sodium channels to promote alveolar fluid clearance in vivo. Am J Physiol Lung Cell Mol Physiol. 2012, 302 (11): L1167-L1178. 10.1152/ajplung.00038.2012. PubMedPubMedCentralCrossRef
- The effects of salbutamol on epithelial ion channels depend on the etiology of acute respiratory distress syndrome but not the route of administration
Pedro L Silva
Raquel S Santos
Paulo J Miranda
Peter M Spieth
Marcelo M Morales
Marcelo Gama de Abreu
Patricia RM Rocco
- BioMed Central
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