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

Abstract

Hepato-splanchnic 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 hepato-splanchnic and pulmonary blood flow, immune responses, and microbiome implicate common pathogenic mechanisms across these vascular networks. Hepato-splanchnic 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 pro-inflammatory 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 lungs, 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.

Cholestasis-Associated Pulmonary Inflammation, Oxidative Stress, and Tissue Fibrosis: The Protective Role of the Biogenic Amine Agmatine

“…A compelling reason for these differences could be associated with different degrees of liver injury and, consequently, higher levels of cytotoxic molecules such as bile acids and bilirubin in the lung tissue. Moreover, complications such as gut permeability and the translocation of bacterial lipopolysaccharide as a potent activator of the inflammatory response are more prevalent in the later stages of cholestasis in the BDL model [31][32][33]. Hence, as observed in the current study, an enormous increase in lymphocytes, monocytes, neutrophils, IgG, TNF-α, IL-1β, and IL-6 in the BALF was observed on day 28 compared with day 14 after cholestasis induction.…”

“…damage could develop into more severe complications, such as hepato-pulmonary syndrome, if not appropriately managed [31]. There is no specific pharmacological intervention against cholestasis-induced lung injury so far.…”

“…As mentioned, the direct effects of cytotoxic molecules such as bile acids could be involved in these complications [27,28]. However, it is well known that gut permeability is increased in cholestasis/cirrhosis [31][32][33]. Impaired gut permeability could cause an increased level of bacteria and endotoxins in the blood circulation [31][32][33].…”

“…However, it is well known that gut permeability is increased in cholestasis/cirrhosis [31][32][33]. Impaired gut permeability could cause an increased level of bacteria and endotoxins in the blood circulation [31][32][33]. These agents can induce infection and inflammatory response in many organs, including the lung, during cholestasis/ cirrhosis [31].…”

Airway delivery of Streptococcus salivarius is sufficient to induce experimental pulmonary hypertension in rats

“…In addition to PVR, another potential and untapped manifestation of PH is alteration of the gut microbiome and gut metabolic pathways, which have been demonstrated to be associated with a variety of cardiopulmonary diseases, including PH (Marsland et al, 2015;Tang & Hazen, 2017). Several previous studies have reported altered gut microbiome signatures in both patients with PH and numerous experimental PH animal models (Callejo et al, 2018;Hanidziar & Robson, 2021;Kim et al, 2020;Sharma, Oliveira, et al, 2020;Sharma, Stevens, et al, 2020), and gut microbiota elimination by a combination of antibiotics suppresses the development of PH in a SU5416/hypoxia-induced PH rat model (Sanada et al, 2020), indicating the potential lung-gut axis and essential roles of the gut microbiome in pulmonary vascular diseases. Interestingly, although SU5416/hypoxia, hypoxia-, and S. salivarius-induced PH produce obvious alterations in the composition of the gut microbiome, the specific changes are different, suggesting potentially different pathogenic mechanisms for these different PH models.…”