Liver-lung interactions in critical illness

Organ interactions are increasingly recognized as key determinants of the pathogenesis and potential for resolution of tissue injury during critical illness. A paradigm for a systems model that takes into account the modulatory effects of organ interactions and incorporates the expanding number of molecular and cellular pro-inflammatory networks is still lacking. Unifying hypotheses for multiple organ dysfunction during the systemic inflammatory response syndrome have been slow to emerge. The liver plays a central role in the regulation of multiple host defense, immunologic, biochemical, and metabolic functions during sepsis and trauma. However, the liver is relatively inaccessible for clinical study and its function is often non-specifically defined. Consequently, the liver's pathogenetic importance within a regulatory network of mediator and organ interactions during inflammatory responses leading to acute lung injury is poorly appreciated. This review addresses the concept that hepatic performance, broadly defined, represents a point of convergence in which four regulatory elements of the acute inflammatory response interact over a host defense continuum to affect lung function. These regulatory elements include: a) control of systemic endotoxemia, bacteremia, and vasoactive by-products of sepsis and trauma by the gut-liver axis of inflammation, mononuclear phagocytic clearance, and Fc and complement receptor-mediated events; b) production and export of endogenous cytokine and eicosanoid mediators by Kupffer cells, especially in relation to changes in the prevailing hepatic oxygen supply; c) metabolic inactivation and detoxification of such mediators via cell-to-cell interactions at the Kupffer cell-hepatocyte interface; and d) cytokine-driven synthesis of acute-phase proteins that critically modulate metabolism and inflammation. Our goal is to summarize and integrate recent information that sheds light on mechanisms by which hepatic function modulates host defense homeostasis, thereby influencing pulmonary function in the adult respiratory distress syndrome. Liver-lung interactions are presented as a heuristic paradigm of organ interactions that dynamically modulate systemic immunophysiologic responses during critical illness.