Blocking Cyclic Adenosine Diphosphate Ribose-mediated Calcium Overload Attenuates Sepsis-induced Acute Lung Injury in Rats

Abstract

Background:Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality. Intracellular Ca2+ overload plays an important role in the pathophysiology of sepsis-induced ALI, and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca2+ mobilization. The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALI is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALI and whether blocking cADPR-mediated calcium overload attenuates ALI.Methods:Septic rat models were established by cecal ligation and puncture (CLP). Rats were divided into the sham group, the CLP group, and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group. Nicotinamide adenine dinucleotide (NAD+), cADPR, CD38, and intracellular Ca2+ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor (TNF)-α, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities were measured.Results:NAD+, cADPR, CD38, and intracellular Ca2+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca2+ levels (P = 0.007), attenuated lung histological injury (P = 0.023), reduced TNF-α and MDA levels (P < 0.001 and P = 0.002, respectively) and recovered SOD activity (P = 0.031) in the lungs of septic rats.Conclusions:The CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALI.

Increased TLR4 Expression Aggravates Sepsis by Promoting IFN-γExpression in CD38−/−Mice

“…This inflammatory cell infiltration deficiency results in an impaired innate immunity that renders CD38 −/− mice more vulnerable to Gram-positive bacterial infection. In addition, Peng et al have revealed that by blocking the CD38/cADPR/Ca 2+ pathway, heart, liver, lung, and kidney injuries were alleviated in the CLP surgery-induced sepsis mouse model [36]. Shu et al showed that AKI was attenuated in an LPS-induced sepsis mouse model after CD38 was blocked by quercetin injected intraperitoneally [35].…”

CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets

“…Recently, Peng et al demonstrated that the CD38/cADPR pathway was activated in sepsis using a cecal ligation and puncture rat model (Peng, Ai, et al, 2016). They also demonstrated that administration of 8-bromo-cADPR protected organs (heart, liver, kidneys) from sepsis-induced damage (Peng, Ai, et al, 2016; Peng, Zou, et al, 2016). These studies demonstrate that blocking cADPR action and/or CD38 activity may be useful in treating sepsis.…”

miR-128-3p enhances the protective effect of dexmedetomidine on acute lung injury in septic mice by targeted inhibition of MAPK14

“…Excessive inflammatory response induced by sepsis can lead to multiple organ damage and failure. Acute lung injury (ALI) is a common complication of sepsis as lung is particularly sensitive to sepsis damage [3]. ALI is characterized by progressive hypoxemia, enhanced vascular permeability, edema, neutrophil infiltration and lung accumulation, which greatly increases patient morbidity and mortality [4].…”