Innate immunity serves as the rapid and first-line defense against invading pathogens, and this process can be regulated at various levels, including epigenetic mechanisms. The bromodomain and extraterminal domain (BET) family of proteins consists of four conserved mammalian members (BRD2, BRD3, BRD4, and BRDT) that regulate the expression of many immunity-associated genes and pathways. In particular, in response to infection and sterile inflammation, abnormally expressed or dysfunctional BETs are involved in the activation of pattern recognition receptor (e.g., TLR, NLR, and CGAS) pathways, thereby linking chromatin machinery to innate immunity under disease or pathological conditions. Mechanistically, the BET family controls the transcription of a wide range of proinflammatory and immunoregulatory genes by recognizing acetylated histones (mainly H3 and H4) and recruiting transcription factors (e.g., RELA) and transcription elongation complex (e.g., P-TEFb) to the chromatin, thereby promoting the phosphorylation of RNA polymerase II and subsequent transcription initiation and elongation. This review covers the accumulating data about the roles of the BET family in innate immunity, and discusses the attractive prospect of manipulating the BET family as a new treatment for disease.

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The BET family in immunity and disease

Acute kidney injury is a common complication in patients receiving extracorporeal membrane oxygenation (ECMO). The underlying mechanisms are multifactorial including the primary disease, effects of invasive mechanical ventilation, ECMO circuit-related factors and critical illness in general. Renal replacement therapy (RRT) is often required to control fluid balance and is associated with worse outcomes. No consensus exists for indication, timing, modality, and how to best to combine RRT and ECMO. This chapter provides an update of the epidemiology, outcomes and pathophysiology of acute kidney injury in patients receiving ECMO, highlights technical aspects when combining RRT with ECMO, and identifies future research questions.

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Acute kidney injury in ECMO patients.

A novel target to reduce microglial inflammation and neuronal damage after deep hypothermic circulatory arrest

Endotoxemia is a severe inflammation response induced by infection especially bacterial endotoxin translocation, which severely increases mortality in combination with acute colon injury. Bromodomain-containing protein 4 (BRD4) is an important Bromo and Extra-Terminal (BET) protein to participate in inflammatory responses. However, it is still unknown about the specific connection between BRD4 and inflammation-related pyroptosis in endotoxemia colon. Here, through evaluating the mucous morphology and the expression of tight junction proteins such as occludin and ZO1, we found the upregulation of BRD4 in damaged colon with poor tight junction in an endotoxemia mouse model induced by lipopolysaccharides (LPS). Firstly, the BRD4 inhibitor JQ1 was used to effectively protect colon tight junction in endotoxemia. As detected, high levels of pro-inflammation cytokines IL6, IL1β and IL18 in endotoxemia colon were reversed by JQ1 pretreatment. In addition, JQ1 injection reduced endotoxemia-induced elevation of the phosphorylated NF κB and NLRP3/ASC/caspase 1 inflammasome complex in colon injury. Furthermore, activated pyroptosis markers gasdermins in endotoxemia colon were also blocked by JQ1 pretreatment. Together, our data indicate that BRD4 plays a critical role in regulating pyroptosis-related colon injury induced by LPS, and JQ1 as a BRD4 inhibitors can effectively protect colon from endotoxemia-induced inflammation injury.

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JQ1 as a BRD4 Inhibitor Blocks Inflammatory Pyroptosis-Related Acute Colon Injury Induced by LPS.

The mitogen-activated protein kinase (MAPK) pathway controls intestinal epithelial barrier permeability by regulating tight junctions (TJs) and epithelial cells damage. Heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal epithelial barrier function, but the molecular mechanism is not yet clarified. MAPK activation and barrier permeability were studied using monolayers of Caco-2 cells treated with tissue necrosis factor α (TNF-α) transfected with FUGW-HO-1 or pLKO.1-sh-HO-1 plasmid. Intestinal mucosal barrier permeability and MAPK activation were also investigated using carbon tetrachloride (CCl4) administration with CoPP (a HO-1 inducer), ZnPP (a HO-1 inhibitor), CO releasing molecule 2 (CORM-2), or inactived-CORM-2-treated wild-type mice and mice with HO-1 deficiency in intestinal epithelial cells. TNF-α increased epithelial TJ disruption and cleaved caspase-3 expression, induced ERK, p38, and JNK phosphorylation. In addition, HO-1 blocked TNF-α-induced increase in epithelial TJs disruption, cleaved caspase-3 expression, as well as ERK, p38, and JNK phosphorylation in an HO-1-dependent manner. CoPP and CORM-2 directly ameliorated intestinal mucosal injury, attenuated TJ disruption and cleaved caspase-3 expression, and inhibited epithelial ERK, p38, and JNK phosphorylation after chronic CCl4 injection. Conversely, ZnPP completely reversed these effects. Furthermore, mice with intestinal epithelial HO-1 deficient exhibited a robust increase in mucosal TJs disruption, cleaved caspase-3 expression, and MAPKs activation as compared to the control group mice. These data demonstrated that HO-1-dependent MAPK signaling inhibition preserves the intestinal mucosal barrier integrity by abrogating TJ dysregulation and epithelial cell damage. The differential targeting of gut HO-1-MAPK axis leads to improved intestinal disease therapy.

Contributions of HO-1-Dependent MAPK to Regulating Intestinal Barrier Disruption.

https://www.jtcvs.org/article/S0022-5223(18)32495-4/pdf

Cold-inducible RNA-binding protein as a novel target to alleviate blood-brain barrier damage induced by cardiopulmonary bypass.

OBJECTIVES Conventional cardiopulmonary bypass with gravity drainage leads inevitably to haemodilution. Vacuum-assisted venous drainage (VAVD) utilizes negative pressure in the venous reservoir, allowing active drainage with a shortened venous line to reduce the priming volume. The goal of this study was to analyse the efficacy and safety of VAVD. METHODS Data on 19 687 patients (18 681 with gravity drainage and 1006 with VAVD) who underwent cardiac operations between 1 January 2015 and 31 January 2018 were retrospectively collected from a single centre. Propensity matching identified 1002 matched patient pairs with VAVD and gravity drainage for comparison of blood product transfusion rate, major morbidities and in-hospital mortality rates. RESULTS The blood transfusion rate of the VAVD group was lower than that of the gravity drainage group (28.1% vs 35% for red blood cells, 13% vs 18% for fresh frozen plasma and 0.1% vs 1.8% for platelets; P = 0.0009, 0.0020 and <0.0001, respectively). The mean difference (95% confidence interval) between the groups for red blood cells, fresh frozen plasma and platelets was -6.9% (-11.0% to -2.8%), -5.0% (-8.1% to -1.8%) and -1.7% (-2.5% to -0.9%), respectively. No difference was observed regarding the major morbidities of cerebrovascular accidents, acute kidney injury, hepatic failure and perioperative myocardial infarction and the in-hospital deaths between the 2 groups. CONCLUSIONS VAVD was associated with a reduction in blood product transfusions, and an increase in the risk of major morbidities and in-hospital deaths of the VAVD group was not observed.

Vacuum-assisted venous drainage in adult cardiac surgery: a propensity-matched study.

Objectives The intestinal injury during deep hypothermic circulatory arrest (DHCA) is harmful to clinical outcomes. Cold-inducible RNA-binding protein (CIRBP) plays a protective role in hypothermia. The aim of this study was to explore the effects of CIRBP on intestinal barrier during DHCA. Methods Sprague-Dawley (wild type, n = 13) and knockout of Cirbp (Cirbp-/-, n = 8) rats were used in the model of DHCA. The histomorphology of the epithelial barrier was evaluated by haematoxylin-eosin, Chiu's scores, Gram's stain and Ki67. The function of the intestinal barrier was evaluated by serum intestinal fatty acid-binding protein, diamine oxidase and d-lactate. The structure of the epithelial barrier, phosphocreatine-creatine kinase system and adenosine triphosphate were assessed in the intestine. Results The expression of CIRBP significantly increased in the intestine during DHCA. Cirbp-/- rats showed obvious destruction of intestinal barrier after DHCA. Chiu's scores, intestinal fatty acid-binding protein, diamine oxidase and d-lactate significantly increased in the Cirbp-/- group. Ki67 showed that cell proliferation decreased in the Cirbp-/- rats. In the Cirbp-/- group, zonula occludens-1, E-cadherin and occludin levels were significantly decreased, and these proteins either disappeared or redistributed in the monolayer. Besides, Cirbp-/- resulted in decreased levels of creatine kinase B, glycine amidinotransferase, adenosine triphosphate and creatine contents in the intestine, affecting energy metabolism and balance, which is associated with the maintenance of epithelial barrier during acute injury. Conclusions CIRBP is related to the maintenance of the intestinal epithelial barrier during DHCA, which is expected to be a new target for the prevention of intestinal injury.

Qiaoni Zhang

Papers

A novel target to reduce microglial inflammation and neuronal damage after deep hypothermic circulatory arrest

Cold-inducible RNA-binding protein as a novel target to alleviate blood-brain barrier damage induced by cardiopulmonary bypass.

Vacuum-assisted venous drainage in adult cardiac surgery: a propensity-matched study.

Cold-inducible RNA-binding protein maintains intestinal barrier during deep hypothermic circulatory arrest

Quality Management of a Comprehensive Blood Conservation Program During Cardiopulmonary Bypass.