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Role of Acid Sphingomyelinase and IL-6 As Mediators Of Thorax Online First, published on July 27, 2016 as 10.1136/thoraxjnl-2015-208067 Respiratory research ORIGINAL ARTICLE Thorax: first published as 10.1136/thoraxjnl-2015-208067 on 27 July 2016. Downloaded from Role of acid sphingomyelinase and IL-6 as mediators of endotoxin-induced pulmonary vascular dysfunction Rachele Pandolfi,1,2,3 Bianca Barreira,1,2,3 Enrique Moreno,1,2,3 Victor Lara-Acedo,2 Daniel Morales-Cano,1,2,3 Andrea Martínez-Ramas,1,2,3 Beatriz de Olaiz Navarro,4 Raquel Herrero,1,5 José Ángel Lorente,1,5,6 Ángel Cogolludo,1,2,3 Francisco Pérez-Vizcaíno,1,2,3 Laura Moreno1,2,3 ▸ Additional material is ABSTRACT published online only. To view Background Pulmonary hypertension (PH) is frequently Key messages please visit the journal online (http://dx.doi.org/10.1136/ observed in patients with acute respiratory distress thoraxjnl-2015-208067). syndrome (ARDS) and it is associated with an increased risk of mortality. Both acid sphingomyelinase (aSMase) 1Ciber Enfermedades What is the key question? Respiratorias (CIBERES), activity and interleukin 6 (IL-6) levels are increased in ▸ Pulmonary hypertension and right ventricular Madrid, Spain patients with sepsis and correlate with worst outcomes, dysfunction are prominent prognostic features 2 Department of Pharmacology, but their role in pulmonary vascular dysfunction of acute respiratory distress syndrome (ARDS) School of Medicine, pathogenesis has not yet been elucidated. Therefore, the which, given the unclear pathophysiology and Universidad Complutense de Madrid, Madrid, Spain aim of this study was to determine the potential the lack of approved pharmacological therapies, 3Gregorio Marañón Biomedical contribution of aSMase and IL-6 in the pulmonary demand the identification of new therapeutic Research Institution (IiSGM), vascular dysfunction induced by lipopolysaccharide (LPS). targets. Madrid, Spain 4 Methods Rat or human pulmonary arteries (PAs) or Department of Thoracic their cultured smooth muscle cells (SMCs) were exposed What is the bottom line? Surgery, Hospital Universitario ▸ Blockade of either acid sphingomyelinase or de Getafe, Getafe, Spain to LPS, SMase or IL-6 in the absence or presence of a 5Department of Critical Care, range of pharmacological inhibitors. The effects of IL-6 prevents the endothelial dysfunction, the Hospital Universitario de aSMase inhibition in vivo with D609 on pulmonary failure of hypoxic pulmonary vasoconstriction Getafe, Madrid, Spain fl and the hyperresponsiveness to serotonin 6 arterial pressure and in ammation were assessed Universidad Europea, Madrid, induced by lipopolysaccharide (LPS) in vitro Spain following intratracheal administration of LPS. http://thorax.bmj.com/ Results LPS increased ceramide and IL-6 production in and, accordingly, the in vivo administration of fi Correspondence to rat pulmonary artery smooth muscle cells (PASMCs) and the non-speci c acid sphingomyelinase Dr Laura Moreno, Department inhibited pulmonary vasoconstriction induced by inhibitor D609 prevents the development of of Pharmacology, School of phenylephrine or hypoxia (HPV), induced endothelial LPS-induced pulmonary hypertension. Medicine, Universidad Complutense de Madrid, dysfunction and potentiated the contractile responses to Why read on? Madrid 28040, Spain; serotonin. Exogenous SMase and IL-6 mimicked the ▸ This study identifies for the first time that acid [email protected] effects of LPS on endothelial dysfunction, HPV failure sphingomyelinase and IL-6 are not simply and hyperresponsiveness to serotonin in PA; whereas on September 29, 2021 by guest. Protected copyright. Received 17 November 2015 biomarkers of outcome but rather pathogenic Revised 23 June 2016 blockade of aSMase or IL-6 prevented LPS-induced mediators of pulmonary vascular dysfunction Accepted 7 July 2016 effects. Finally, administration of the aSMase inhibitor and, as such, could represent novel therapeutic D609 limited the development of endotoxin-induced PH targets for ARDS secondary to Gram-negative and ventilation-perfusion mismatch. The protective infections. effects of D609 were validated in isolated human PAs. Conclusions Our data indicate that aSMase and IL-6 are not simply biomarkers of poor outcomes but pathogenic mediators of pulmonary vascular dysfunction patients with ARDS frequently develop mild to in ARDS secondary to Gram-negative infections. moderate pulmonary hypertension (PH), which contrasts with the lowered systemic vascular resist- ance that characterises septic shock.45Following this landmark study, pulmonary vascular dysfunc- INTRODUCTION tion, clinically defined as an increase in transpul- Sepsis is the most common risk factor for acute monary gradient and augmented pulmonary respiratory distress syndrome (ARDS).12Acute vascular resistance, has gathered increasing atten- lung injury (ALI)/ARDS is characterised by pulmon- tion. Earlier studies reported an incidence of PH fi To cite: Pandol R, ary oedema and alveolar collapse accompanied by and right ventricular dysfunction of up to 70%.6 In Barreira B, Moreno E, et al. Thorax Published Online hypoxic pulmonary vasoconstriction (HPV) failure, line with this, it has been shown that injurious First: [please include Day resulting in ventilation-perfusion mismatch and mechanical ventilation is an important cause of pul- Month Year] doi:10.1136/ severe arterial hypoxaemia. Nearly 40 years ago, monary vascular injury in patients and in animal thoraxjnl-2015-208067 Zapol and Snider described for the first time3 that models of ALI/ARDS.7 However, in the setting of Pandolfi R, et al. Thorax 2016;0:1–12. doi:10.1136/thoraxjnl-2015-208067 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& BTS) under licence. Respiratory research mechanical ventilation with lung protective strategies, pulmon- Finally, the efficacy of an aSMase inhibitor, D609, was tested in Thorax: first published as 10.1136/thoraxjnl-2015-208067 on 27 July 2016. Downloaded from ary vascular dysfunction is still a prominent feature, with a vivo in a rat model of ALI induced by intratracheal instillation prevalence of 20–25%, and is independently associated with of LPS, used as a model of direct lung injury induced by poor outcomes in patients with ARDS.89Taken together, these Gram-negative bacteria. studies suggest that PH and right ventricular dysfunction can be caused not only by injurious mechanical ventilation but also by MATERIAL AND METHODS other mechanisms, including local alveolar hypoxia, inflamma- An expanded Methods section is available in the online supple- tion and those associated with infection in ARDS.49 mentary material. The mechanisms leading to acute PH in these patients are complex and most likely depend on the underlying cause of Vessel and cell isolation ARDS. However, endothelial dysfunction, hypoxia and imbal- PA were isolated from male Wistar rats or human lung tissue, as ance of endogenous vasoactive factors, with increased produc- previously described.72829Freshly isolated PASMCs and tion of pulmonary vasoconstrictors (endothelin 1, thromboxane primary cell cultures were obtained by enzymatic digestion, as 28 29 A2 or serotonin) over vasodilators (nitric oxide (NO) or prosta- described previously. cyclin), are thought to play a major role.45Given the associ- ation between infection and pulmonary vascular dysfunction in PASMCs or whole pulmonary artery organ culture patients with ARDS, it is tempting to speculate that Rat or human PA rings or rat PASMCs were pretreated with dif- inflammation-mediated pulmonary vasoconstriction may also ferent pharmacological inhibitors or small interfering RNAs contribute to the increase in pulmonary artery pressure (PAP) in (siRNAs) before being exposed to LPS (1 μg/mL; Escherichia coli patients with ARDS. 055:B5), bacterial SMase (0.1 U/mL; Bacillus cereus) or IL-6 Interleukin 6 (IL-6) and NO are two well recognised inflam- (30 ng/mL) for 24 hours, as detailed in the online supplementary matory mediators upregulated in sepsis and ARDS.10 11 material. 24 hours later, cell viability was evaluated by the Overproduction of NO by inducible NO synthase (iNOS) is 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide believed to play a pivotal role in the reduced vascular contractil- (MTT) assay30 and culture medium was frozen until further ity in endotoxin shock. However, PH develops despite iNOS analysis. induction in pulmonary arteries (PAs).12 Moreover, the inhib- ition of NOS activity seems to improve the general systemic Ceramide content detection by immunofluorescence haemodynamic situation but at the cost of raised pulmonary vas- Ceramide content in freshly isolated PASMCs was quantified by cular resistance13 14 and increased mortality.15 On the other immunocytochemistry, as previously described.29 hand, IL-6 is one of the most relevant biomarkers in sepsis. Although IL-6 can activate both proinflammatory and anti- Recording of vascular reactivity inflammatory pathways, IL-6 levels correlate with mortality risk PA rings were mounted in a wire myograph and exposed to from sepsis and ARDS.11 Interestingly, while IL-6 increases hypoxia. Dose–response curves to serotonin, phenylephrine, iNOS activity in aortic smooth muscle cells16 and it is associated endothelin 1 (ET-1) or acetylcholine were performed by cumula- with a drop in systemic blood pressure in patients with septic tive addition, detailed in the online supplementary material.28 29 http://thorax.bmj.com/ shock,17 the levels of IL-6 correlate with PAP in patients with PH secondary to COPD
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