Postoperative Remote Lung Injury and Its Impact on Surgical Outcome

Lin Chen; Hailin Zhao; Azeem Alam; Emma Mi; Shiori Eguchi; Shanglong Yao; Daqing Ma


BMC Anesthesiol. 2019;19(30) 

In This Article

Mechanisms of Postoperative Remote Lung Injury

Remote lung injury often occurs following major surgery due to traumatic injury to primary organs that triggers systemic inflammation[13] (Figure 1). Pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs) molecules have been shown to play critical roles in mediating detrimental organ cross-talk during the postoperative period.

Figure 1.

Molecular mechanisms of remote lung injury following other organ injury or disease conditions. Key cytokines involved in lung injury are IL-6, IL-8 and TNF-α, which are induced by acute kidney injury (AKI), cardiopulmonary bypass, renal ischaemia-reperfusion injury, bilateral nephrectomy, transfusion-related acute lung injury and mechanical ventilation. Ischaemic AKI triggers the production of TNF-α which, upon binding to TNFR1, results in NF-κB activation and pulmonary apoptosis. Epithelial cell apoptosis is caspase-3 dependent and can occur following AKI, haemorrhagic shock, sepsis, hepatopulmonary syndrome, acute liver disease and cardiopulmonary bypass, while capillary endothelial cell apoptosis is independent of caspase. Pulmonary epithelial or capillary endothelial cell apoptosis leads to alveolar-capillary barrier dysfunction, causing the accumulation of protein rich fluid in alveoli and subsequent pulmonary oedema. HMGB1 binds to TLR4, leading to the activation of NAD(P) H oxidase in neutrophils, release of ROS, neutrophil infiltration and pulmonary oedema. Derangement of the alveolar capillary barrier causes the release of cytokines and chemokines, facilitating further neutrophil recruitment and the subsequent release of proteases, ROS and cytokines which further damage the barrier and worsen pulmonary oedema (Modified and reproduced with permission) (Springer Nature; Nature Reviews Nephrology) [13]


Traumatic tissue injury, for example during surgery, causes the release of inflammatory cytokines locally which then spread systemically and subsequently result in organ injury including lung injury. The release of cytokines can be detected in patients after cardiac surgery. Prondzinsky et al.[14] demonstrated that interleukin-6 (IL-6) in plasma was increased in patients after cardiopulmonary bypass (CPB) surgery. Furthermore, the authors found that the correlation between bypass duration and IL-6 is higher in the CPB-coronary artery bypass graft group than in the CPB-percutaneous coronary intervention group, suggesting that surgical trauma contributed to inflammatory response independent of CPB. An increase in the concentration of IL-1β and IL-6 following renal ischaemia-reperfusion injury and bilateral nephrectomy had been noted, whilst IL-6 was shown to play a vital role in causing lung injury after acute renal failure.[15,16] Vlaar et al.[17] reported that "aged" platelet transfusion induced IL-6 release in animal lung tissue, whilst using a "two-hit" model the authors demonstrated that the supernatant of platelet concentrates were responsible for pulmonary inflammation. It has also been shown that TRALI is associated with both systemic and pulmonary inflammation compared to the control cohorts, as indicated by higher levels of IL-6 and IL-8 in the plasma and bronchoalveolar lavage fluid (BALF).[18,19]


DAMPs are endogenous mediators that play critical roles in various diseases. It is thought that DAMPs are transported to the lungs via circulation from organs damaged perioperatively. Although the role of DAMPs in lung injury is not completely understood, several well-described DAMPs are involved in the pathogenesis of postoperative remote lung injury.[20,21]

High-mobility group box-1 (HMGB1). Injured cells and immune cells including macrophages release HMGB1 after surgery, which triggered the production of various pro-inflammatory cytokines. Various surgical procedures, including gastrointestinal surgery and CPB, may induce release of HMGB1.[20,22] A study demonstrated that there was an increase in serum HMGB1 after thoracic oesophagectomy, whilst the peak concentration of HMGB1 correlated with length of ICU stay and duration of mechanical ventilation.[23] Moreover, treatment with anti-HMGB1 antibody alleviated lung injury by reducing inflammatory cytokines and inhibiting NF-κB activation.[24] The HMGB1/toll-like receptor 4 (TLR4) signalling pathway had been shown to trigger neutrophil NAD(P) H oxidase activation, which facilitated the release of reactive oxygen species (ROS).[25] An increase in HMGB1 was also found in ALI induced by liver ischaemia/reperfusion (I/R) injury, whereby binding of HMGB1 to its receptor TLR4 and the subsequent activation of downstream signalling pathways contributed to the development of lung injury.[26] Yamamoto et al.[27] demonstrated that HMGB1 was released into the circulation system after hepatic I/R injury and was related to ALI. Furthermore, they used an HMGB1 absorption column to reduce the concentration of HMGB1 in serum, which attenuated both liver injury and lung injury.

NOD-like receptor protein 3 (NLRP3). NLRP3 is a member of the NLR family that participates in inflammatory response under various cellular stresses. Upon activation, an inflammasome complex is formed which facilitates the maturation and secretion of IL-1β and IL-18, mediated by activated caspase-1.[28,29] Moreover, the interaction between extracellular histones and NLRP3 inflammation also mediates ALI.[30]

NLRP3 expression is increased in the lung following mechanical ventilation. Kuipers et al.[31] demonstrated that 5 h of mechanical ventilation upregulate NLRP3 mRNA expression in alveolar macrophages from patients. In addition, the increase of NLRP3 mRNA resulted in upregulation of caspase-1 expression and an increase in uric acid level. Compared to the wild-type group, NLRP3 knock-out mice experienced less lung injury after high tidal volume mechanical ventilation. Mechanistic insight was provided by Wu et al., they demonstrated that cyclic stretch activated NLRP3 inflammasome and increased IL-1β production in alveolar macrophages, mediated by mitochondria-generated ROS. Moreover, mechanical ventilation was shown to activate NLRP3 inflammasome in mouse alveolar macrophages and increase IL-1β release in vivo. However, pulmonary inflammatory injury induced by mechanical ventilation was alleviated by IL-1β neutralization.[21] The evidence indicated that macrophage NLRP3 inflammasome may bridge the gap between mechanical stretch and the release of IL-1β. Recently, it was reported that autophagy in alveolar macrophages contributed to the pathogenesis of lung injury during mechanical ventilation through activation of the NLRP3 inflammasome.[32]

Haemorrhagic shock is capable of activating NLRP3 inflammasome. In lung endothelial cells, ROS derived from haemorrhagic shock-activated NAD(P) H oxidase induced inflammasome activation and IL-1β secretion. Inflammasome activation is amplified by ROS released by neutrophils which further enhance NAD(P) H oxidase activation.[33] Imbalance of NLRP3 inflammasome activation and its negative-feedback regulator pryin also contributed to ALI following haemorrhagic shock.[34]

Heat shock proteins (Hsp). Hsp are another type of DAMPs released by cells under stress and noxious stimuli in a process known as stress protein response (SPR). SPR can be activated by hyperthermia and various environmental insults such as oxidative stress toxins.[35] Increasing evidence indicated that Hsp were involved in the process of lung injury. The presence of extracellular Hsp72 (eHsp72) has been reported in the pulmonary oedema fluid of patients with ALI. In addition, eHsp72 release was found in mice under SPR activation.[36] Chase et al.[37] further validated the relationship between Hsp72 and lung inflammation. Intratracheal instillation of Hsp72 caused TLR-4 dependent cytokine release and neutrophil recruitment in BALF. In vitro, Hsp72 directly activated airway epithelial cells and induced upregulation of IL-8 expression, which was NF-κB dependent. Hsp70 was able to trigger pro-inflammatory signals in macrophages through toll-like receptors.[38] Various studies have reported that in patients after major surgery, there was an increased release of Hsp70 into the circulation.[39–41] Interestingly, circulating Hsp70 after major surgery was associated with an increased expression of IL-6 in plasma, whilst both were found to be involved in postoperative organ dysfunction.[40] However, the concentration of Hsp70 declined immediately after surgical insult, suggesting that it only initiated injurious processes upon interaction with its receptor.

Apoptosis and Necroptosis

Apoptosis in inflammatory cells and alveolar cells mediated ALI after haemorrhagic shock.[42] In an indirect ALI mouse model caused by haemorrhagic shock and sepsis, lung inflammation was found to be characterized by caspase-3 dependent lung epithelial cell apoptosis.[43,44] In addition, caspase-3 dependent pulmonary injury was evident during the pathogenesis of hepatopulmonary syndrome, whilst lung injury secondary to liver injury could be alleviated with administration of caspase-3 inhibitor Z-DEVD-FMK.[45] Pulmonary injury induced by intestinal I/R was also characterized by increased TUNEL positive cells and caspase-3 activity in the lung.[46] Another study demonstrated that ischaemic acute kidney injury triggered tumor necrosis factor-α (TNF-α) production which, through binding to its receptor TNFR1, resulted in pulmonary apoptosis by activating NF-κB.[47] However, in term of programmed cell death, pulmonary epithelial and endothelial cells react differently. Barlos et al. proved that apoptosis of epithelial cells was caspase-dependent, whilst endothelial cells underwent apoptosis in an apoptosis-inducing factor-dependent, caspase-independent manner.[48] Surgical operations such as cardiopulmonary bypass may also cause pulmonary inflammatory response. Increased activity of caspase-3 in the lung has been noted during this process.[49]

Recently, it was reported that regulated necrosis also participates in remote lung injury. Two different forms of regulated necrosis, necroptosis and parthanatos, were found to be present in lung injury after kidney transplantation in rats. TNF-α was responsible for activation of key elements of necroptosis and parthanatos in lung epithelial cells, whilst blocking their function with inhibitors alleviated remote lung injury.[50]