Opioids for the relief of acute respiratory distress syndrome: Endomorphins are the μ kids on the block!

Abstract

The onset of acute respiratory distress syndrome (ARDS) is often sudden, severe and rapidly progressive, responsible for ∼10% of intensive care unit admissions. Acute respiratory distress syndrome is underscored by an inflammatory process that promotes a leaky pulmonary barrier, which can prove fatal. Pulmonary oedema impairs gas exchange, with resultant hypoxaemia, which further complicates the management of patients. In a recent systematic review of current pharmacological agents used in the treatment of ARDS, including corticosteroids, surfactants, N-acetylcysteine, statins and β-agonists, it was determined that none of these pharmacotherapies robustly mitigated dependence upon mechanical ventilation or reduced mortality (Lewis, Pritchard, Thomas, & Smith, 2019). There is impetus in the pursuit of new therapeutic strategies for the treatment of ARDS. Opioids are a cornerstone of pain relief. In addition, beyond their analgesic properties, there is a growing appreciation of their potential use and versatility as a therapeutic option in a variety of diseases. Activation of μ-opioid receptors promotes vascular endothelial cell proliferation and angiogenesis and regulates inflammation, factors that are pertinent to ARDS. In this issue of Experimental Physiology, Ji and Wang (2019) provide evidence that μ-opioid receptor activation ameliorates pathophysiological features in an animal model of ARDS. Tracheal instillation of lipopolysaccharide in adult mice evoked pulmonary injury characterized histologically and by evidence of pulmonary oedema and increased protein concentration in the bronchoalveolar lavage fluid, with augmented levels of inflammatory mediators (interleukin-1β and tumour necrosis factor-α) and increased myeloperoxidase activity, a surrogate marker of neutrophil infiltration. Interestingly, i.v. treatment of mice with the μ-opioid selective agonist endomorphin-1 immediately after lipopolysaccharide instillation yielded tangible pulmonary protection. All markers of lung injury and inflammation were substantially reduced compared with mice administered lipopolysaccharide alone. Furthermore, the authors convincingly demonstrated that the beneficial effects of endomorphin-1 are mediated via the phosphatidylinositol 3 kinase (PI3K)/Akt signalling pathway, given that pretreatment with wortmannin, a PI3K inhibitor, given i.v. 90 min before lipopolysaccharide and endomorphin-1 administration, was shown to obstruct the attenuating effects of endomorphin-1, thereby facilitating the development of ARDS-like features similar to those observed with lipopolysaccharide administration alone. Consistent with this observation, phosphorylated Akt protein abundance in pulmonary tissue was increased in endomorphin-1-treated mice, and this was prevented by upstream inhibition of PI3K with wortmannin. The study by Ji and Wang (2019) complements and extends previous work revealing that μ-opioid activation is effective in attenuating lung injury in rats via downregulation of the pro-inflammatory transcription factor nuclear factor-κB (Zhang, Du, Zhou, Wang, & Li, 2014), a downstream target of the PI3K/Akt signalling cascade. Together, these studies provide a mechanistic link supporting anti-inflammatory actions of μ-opioid receptor activation relevant to pulmonary disease, albeit that specific cell types were not characterized in the study by Ji and Wang (2019). Opioid–immune system interaction is well recognized, and μ-opioid agonists are known to exert anti-inflammatory actions in peripheral organs, such as the gut (Anselmi et al., 2015). Immune cells express surface μ-opioid receptors and secrete endogenous opioid peptides, which act on peripheral targets, for example, serving to suppress inflammatory pain. However, interactions can be complex, and there is a dearth of controlled trials assessing the clinical efficacy of opioids in inflammatory diseases (Plein & Rittner, 2018). Of concern, immunosuppressant actions of opioids can serve to increase vulnerability to infection, which is a major issue in the context of ARDS, with risk of sepsis associated with high mortality. The serious side-effects of traditional opioids are well recognized and have prompted considerable interest in the development of highly selective potent agonists with profiles that are safer compared with currently available therapeutic options. The central respiratory depressant actions of μ-opioid agonists, which can be compounded further by high concentrations of inspired oxygen is a major limiting factor in their use, although new compounds with limited respiratory depressant effects but maintained analgesic properties and co-treatment strategies are emerging (van der Schier, Roozekrans, van Velzen, Dahan, & Niesters, 2014). In the context of ARDS, a peripherally acting, potent selective μ-opioid receptor agonist might be a preferred strategy in the future, but even so one must recognize the potential action of such agents on peripheral structures, such as the carotid bodies, with a potential to depress chemoreflex control of breathing and the circulation, clearly contraindicated for most patients, but especially those with manifest pulmonary malaise, albeit less troubling perhaps in the context of mechanically ventilated patients in the intensive care unit. To add further complexity, it is worth noting that opioid abuse can trigger ARDS. Also, patients in intensive care are typically prescribed sedatives and opioids, which are known to prolong the duration of mechanical ventilation and delay progression to spontaneous breathing, such that new opioid-based tailored therapy for ARDS in this setting might be an especially difficult prospect. To conclude, the study of Ji and Wang (2019) illustrates that μ-opioid receptor activation mitigates key pathophysiological traits of bacterially induced lung injury, paving the way for the exploration of their potential application in the treatment of ARDS. Time will tell whether opioid therapy provides for no pain with pulmonary gain. If so, then endomorphin-1 or new-generation derivatives could emerge as ‘μ kids on the block’ in the treatment and management of ARDS. None declared.