Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Anesthesia, Critical Care and Pain Medicine, Center for Inflammation Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Am J Physiol Gastrointest Liver Physiol. 2021 Aug 1;321(2):G200-G212. doi: 10.1152/ajpgi.00406.2020. Epub 2021 Jun 9.
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.
肝脾和肺血管构成了同源的、高度可比的网络，与外部环境融为一体。由于与“进食和呼吸”的强制性需求相关的功能，这些器官经常受到感染风险、抗原和外源性物质暴露等环境挑战的影响。宿主对这些刺激的反应需要既具有保护性又需要受到严格调控。这些功能得益于肝脏和肺部的双重高低压血液供应，以及驻留免疫细胞和信号通路的耐受性特征。肝脾和肺血流、免疫反应和微生物组的失调暗示了这些血管网络中共同的致病机制。肝脾疾病，如肝硬化和门静脉高压，经常影响肺部并扰乱肺循环和氧合。相反的情况也在肺部疾病导致肝功能障碍时观察到。其他人，包括我们，已经描述了在涉及细胞外嘌呤（例如 ATP、ADP）的肝脏和肺部炎症中失调的细胞信号转导的共同特征，这些嘌呤要么是外源性产生的，要么是内源性产生的。这些代谢物作为危险信号，当细菌释放或细胞应激时，会在肠道/肝肺血管中引起促炎和促血栓信号。这些危险信号的抑制和器官保护在很大程度上取决于血管和免疫细胞表达的外核苷酸酶（CD39 和 CD73）的活性，这些酶将 ATP 和 ADP 转化为抗炎的腺苷。然而，在许多涉及肠道、肝脏和肺部的炎症性疾病中，这些保护机制受到损害，导致组织损伤持续存在。我们提出，专门针对异常嘌呤能信号的干预措施可能预防和/或改善肠道/肝肺轴的炎症性疾病。
