Oxycodone attenuates vascular leak and lung inflammation in a clinically relevant two-hit rat model of acute lung injury

Highlights

• Oxycodone improves pulmonary epithelial barrier permeability in in a two-hit model of acute lung injury.

• Oxycodone improves endothelial barrier dysfunction in vivo and in vitro at the level of tight junctions and AQPs.

• Oxycodone inihibits inflammation and apoptosis via suppression of TLR4/NF-κB pathway.

Abstract

Background

Oxycodone is a synthetic opioid receptor agonist that exerts antinociceptive activity via κ-, μ- and δ-opioid receptors (KOR, MOR and DOR, respectively). Activation of MOR has been reported to provide protection against acute lung injury (ALI). We hypothesized that pretreatment with oxycodone would attenuate lung injury at the level of alveolar tight junctions (TJs) and aquaporins (AQPs) and investigated this possibility in a two-hit model of ALI induced by lipopolysaccharide (LPS) and mechanical ventilation (MV).

Method

Male Sprague Dawley rats and A59 cells were divided into 6 groups: the control group, ALI group, oxycodone-pretreated group, and oxycodone/κ-, μ-, or δ-opioid receptor antagonist-pretreated groups. The rats were pretreated with oxycodone 30 min before intravenous injection of LPS and then allowed to recover for 24 h prior to MV, establishing a two-hit model of ALI. The cells were similarly treated with oxycodone (with or without antagonists) 30 min after exposure to lipopolysaccharide. The cells were cyclically stretched 24 h later to mirror the in vivo MV protocol.

Results

Oxycodone alleviated the histological lung changes in the rats with ALI and decreased pulmonary microvascular permeability both in vivo and in vitro. Oxycodone upregulated the expression of claudin-5, ZO-1, AQP1, and AQP5 but downregulated the expression of TNF-α, IL-1β, TLR4, NF-κB, MMP9, and caspase-3 and suppressed endothelial apoptosis in vivo and in vitro. These protective effects of oxycodone were partly eliminated by KOR and MOR antagonists but not by DOR antagonists.

Conclusion

Oxycodone pretreatment appears to act via κ- and μ-opioid receptors to ameliorate LPS- and MV-induced lung injury by suppressing inflammation and apoptosis, and this protective effect might be mediated through the inhibition of the TLR4/NF-κB pathways.

Introduction

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a disorder characterized by an acute onset of noncardiogenic pulmonary oedema and hypoxemia. Despite decades of improvements in therapy, the mortality of ARDS remains as high as 40% [1]. The pathology of ALI is characterized by inflammatory infiltration and high-permeability pulmonary oedema. PMVECs (pulmonary microvascular endothelial cells) are prime targets of inflammatory cytokines [2]. Vascular endothelial barrier dysfunction in response to the inflammatory response leads to vascular leakage and pulmonary oedema. As important components of special intercellular structures, tight junctions (TJs) play a protective role in preserving barrier integrity [3]. In addition, aquaporins (AQPs) are essential for maintaining normal barrier permeability. AQPs are a family of transmembrane water channels that facilitate the movement of water across membranes in response to changes in fluid osmolarity [4]. Among the AQPs, AQP1 and AQP5 play critical roles in the absorption of alveolar fluid. Recently, emerging studies have revealed the essential roles of AQP1 and AQP5 in enhancing the clearance of alveolar fluid [5].

Sepsis is an important cause of ARDS. Mechanical ventilation (MV) is typically used as respiratory support and life-saving therapy in septic patients [6]. However, MV also produces functional and structural disturbances in the lung, known as ventilator-induced lung injury (VILI), which can exacerbate pre-existing lung injury resulting from an initializing event (e.g., sepsis-induced ALI), leading to a “second hit” of ALI [7]. Patients receiving MV in the operating room or intensive care unit require sedative medications or analgesics [8]. Opioids are a class of sedatives used in the perioperative period [9]. Although necessary to support critically ill patients undergoing MV, the use of opioids in ALI patients remains controversial.

As a multiple opioid receptor agonist, oxycodone is routinely used as a sedative. The effects of opioids are achieved by their interactions with surface receptors, including κ-, δ-, and μ-opioid receptors (MOR, DOR and KOR, respectively) [9]. Compared with other opioids, oxycodone has a stronger affinity for κ receptors [10]. Although distributed mainly in the nervous system, opioid receptors have also been proven to be expressed in endothelial cells [11]. Thus, opioids have been shown to confer organ protection in sepsis-induced lung injury, myocardial ischaemia/reperfusion, and ischaemic brain injury [12], [13], [14], [15]. Recent evidence has recapitulated the lung protection by opioids under septic conditions. Ji et al. proved that activation of the μ-opioid receptor could attenuate LPS-induced ALI by the PI3K/Akt pathway [12]. Zhang et al. revealed that remifentanil (μ-opioid receptors agonist) ameliorated LPS-Induced ALI through inhibiting inflammatory cytokines production [13]. Kong et al. reported oxycodone inhibited hippocampal neurons apoptosis induced by oxygen-glucose deprivation/recovery in rats [14]. Whether oxycodone exerts similar effects in ALI remains unclear, and to date, no research has addressed the effect of oxycodone on pulmonary barrier integrity. Due to the complex, multifactorial pathobiology of ALI, we established a two-hit ALI model induced by LPS plus MV to mimic VILI in septic patients. Our research is the first to explore the lung-protective effects of oxycodone at the level of TJs and AQPs in a clinically relevant ALI model.