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)-μ, 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-μ 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.

• Authors: Qian-Yi Peng, Yu Zou, Li-Na Zhang, Mei-Lin Ai, Wei Liu, Yu-Hang Ai
• Journal: Chinese medical journal (Chin Med J (Engl)) Vol. 129 Issue 14 Pg. 1725-30 (Jul 20 2016) ISSN: 2542-5641 [Electronic] China
• PMID: 27411462 (Publication Type: Journal Article)

Chemical References

• 8-bromo-cyclic-ADP-ribose
• Tumor Necrosis Factor-alpha
• Cyclic ADP-Ribose
• Malondialdehyde
• Superoxide Dismutase
• ADP-ribosyl Cyclase 1
• Calcium

Topics

• ADP-ribosyl Cyclase 1 (metabolism)
• Acute Lung Injury (chemically induced, drug therapy)
• Animals
• Calcium (metabolism)
• Cyclic ADP-Ribose (analogs & derivatives, antagonists & inhibitors, metabolism, therapeutic use)
• Male
• Malondialdehyde (metabolism)
• Rats
• Rats, Sprague-Dawley
• Sepsis (complications)
• Superoxide Dismutase (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)