Synapomorphic features of hepatic and pulmonary vasculatures include comparable purinergic signaling responses in host defense and modulation of inflammation

Abstract

Hepatosplanchnic and pulmonary vasculatures constitute synapomorphic, highly comparable networks integrated with the external environment. Given functionality related to obligatory requirements of "feeding and breathing," these organs are subject to constant environmental challenges entailing infectious risk, antigenic and xenobiotic exposures. Host responses to these stimuli need to be both protective and tightly regulated. These functions are facilitated by dualistic, high-low pressure blood supply of the liver and lungs, as well as tolerogenic characteristics of resident immune cells and signaling pathways. Dysregulation in hepatosplanchnic and pulmonary blood flow, immune responses, and microbiome implicate common pathogenic mechanisms across these vascular networks. Hepatosplanchnic diseases, such as cirrhosis and portal hypertension, often impact lungs and perturb pulmonary circulation and oxygenation. The reverse situation is also noted with lung disease resulting in hepatic dysfunction. Others, and we, have described common features of dysregulated cell signaling during liver and lung inflammation involving extracellular purines (e.g., ATP, ADP), either generated exogenously or endogenously. These metabokines serve as danger signals, when released by bacteria or during cellular stress and cause proinflammatory and prothrombotic signals in the gut/liver-lung vasculature. Dampening of these danger signals and organ protection largely depends upon activities of vascular and immune cell-expressed ectonucleotidases (CD39 and CD73), which convert ATP and ADP into anti-inflammatory adenosine. However, in many inflammatory disorders involving gut, liver, and lung, these protective mechanisms are compromised, causing perpetuation of tissue injury. We propose that interventions that specifically target aberrant purinergic signaling might prevent and/or ameliorate inflammatory disorders of the gut/liver and lung axis.

Keywords: acute respiratory distress syndrome; inflammation; liver failure; purinergic signaling; sepsis.

Graphical abstract

Figure 1.

Endothelium-mediated protection from aberrant nucleotide signaling. A: during homeostasis, ectonucleotidases CD39 and CD73 in concert hydrolyze extracellular ATP and ADP into adenosine. B: in inflammatory states, ectonucleotidase expression may be decreased and quantity of circulating nucleotides increased. Elevated extracellular nucleotides provoke vascular inflammation and generation of platelet-neutrophil aggregates. Components of this figure were created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.

Figure 2.

Gut-liver-lung axis during homeostasis and liver cirrhosis. A: during homeostasis, most mesenteric venous blood passes through the liver before it reaches pulmonary circulation. B: in patients with cirrhosis and portal hypertension, mesenteric blood rich in bacterial products can reach pulmonary circulation directly via porto-systemic shunts. Mesenteric lymph reaches pulmonary circulation via thoracic duct. In the setting of abdominal infection, these anatomic connections between gut and lung facilitate development of acute lung injury. Components of this figure were created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.