Probing the toxicity of mesenteric lymph in critical illness

Abstract

Background: Critical illness (CI) is a major global health burden and the leading cause of death in the intensive care unit. It can originate from a wide range of aetiologies and often progresses through a common pathway of increasing severity - systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). However, the exact pathophysiological mechanism is still not fully understood, and supportive care is still the mainstay of treatment. Cytokines and damage-associated molecular pattern (DAMP) molecules are regarded as important mediators in CI. Mesenteric lymph (ML) has been recognised as an important channel in carrying toxic mediators in MODS. Hypothesis: The ML is a major anatomical route for DAMPs and cytokines traffic into the circulation during acute CI states and can influence lung end-organ gene expression. Method: Three different rodent models of CI (acute pancreatitis (AP), sepsis, and intestinal ischemia-reperfusion injury) were established. Ten cytokines, three nucleic acid DAMPs and two protein DAMPs were measured in plasma and ML at the three different collection time points. The final gene expression changes in the key end-organ of the lung for these three CI models were also analysed with or without ML drainage. Finding: Plasma cytokines and DAMPs were elevated in circulation during acute CI, and they followed different patterns in each disease model. The drainage of ML variably attenuated or altered these plasma elevations although the ML itself did not carry all these altered plasma cytokines and DAMPs. Significant gene expression changes were noted in the lungs during acute CI, and they were different between each disease model. The ML drainage caused significant alteration of gene expression in the lung in each model. Conclusion: ML is an important and underappreciated physiological channel that can carry important mediators such as cytokines in a wide range of common CI states (and certain DAMPs in AP). Drainage of ML was able to attenuate or alter the circulatory cytokines and DAMPs profile during CI. All three CI models had altered lung gene expression. The drainage of ML altered the expression profile of the diseased lung genes during CI.