Postoperative remote lung injury and its impact on surgical outcome

Abstract

Postoperative remote lung injury is a complication following various surgeries and is associated with short and long-term mortality and morbidity. The release of proinflammatory cytokines, damage-associated molecular patterns such as high-mobility group box-1, nucleotide-biding oligomerization domain (NOD)-like receptor protein 3 and heat shock protein, and cell death signalling activation, trigger a systemic inflammatory response, which ultimately results in organ injury including lung injury. Except high financial burden, the outcome of patients developing postoperative remote lung injury is often not optimistic. Several risk factors had been classified to predict the occurrence of postoperative remote lung injury, while lung protective ventilation and other strategies may confer protective effect against it. Understanding the pathophysiology of this process will facilitate the design of novel therapeutic strategies and promote better outcomes of surgical patients. This review discusses the cause and pathology underlying postoperative remote lung injury. Risk factors, surgical outcomes and potential preventative/treatment strategies against postoperative remote lung injury are also addressed.

Keywords: Cytokine; Pathophysiology; Remote lung injury; Risk factor; Therapeutic strategy.

Fig. 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]

Fig. 2

Primary kidney injury and remote lung injury. Primary kidney injury causes the release of DAMP molecules, which in turn results in the upregulation of inflammatory responses in the distant lung. Immune cells, such as neutrophils, monocytes and T cells, contribute to the exacerbation of remote lung injury (Modified and reproduced with permission) (Springer Nature; Nature Reviews Nephrology) [13]

Fig. 3

Lung oedema due to functional loss of kidney. Factors associated with the initiation of remote lung injury include the accumulation of toxic by-products, enhanced cytokine release and impaired metabolism due to an imbalance of mediators secreted in kidney injury. These insults cause an increase in pulmonary vascular permeability and, therefore, oedema. Key cytokines in the pathogenesis of remote lung injury following AKI are IL-6 and IL-8, which lead to endothelial dysfunction and pulmonary oedema (Modified and reproduced with permission) (Springer Nature; Nature Reviews Nephrology) [13]