PMID- 27589725 OWN - NLM STAT- MEDLINE DCOM- 20170323 LR - 20181113 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 17 IP - 9 DP - 2016 Aug 30 TI - Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9. LID - 10.3390/ijms17091425 [doi] LID - 1425 AB - The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this study was to investigate the role and mechanism of mtDNA release on lipopolysaccharide (LPS) induced acute lung injury (ALI) and systemic inflammation. Following LPS injection, plasma mtDNA copies peak at 8 h. Compared with wild-type (WT) mice, mtDNA in toll like receptor 4 knockout (TLR4 KO) mice were significantly decreased. MtDNA intra-peritoneal administration causes apparent ALI as demonstrated by increased lung injury score, bronchoalveolar lavage fluid (BALF) total protein and wet/dry (W/D) ratio; mtDNA injection also directly provokes systemic inflammation, as demonstrated by increased IL-1beta, IL-6, high-mobility group protein B1 (HMGB1) level; while nuclear DNA (nDNA) could not induce apparent ALI and systemic inflammation. However, compared with WT mice, TLR4 KO could not protect from mtDNA induced ALI and systemic inflammation. Specific TLR9 inhibitor, ODN 2088 pretreatment can significantly attenuate mtDNA induced ALI and systemic inflammation, as demonstrated by improved lung injury score, decreased lung wet/dry ratio, BALF total protein concentration, and decreased systemic level of IL-1beta, IL-6 and HMGB1. MtDNA administration activates the expression of p-P38 mitogen-activated protein kinases (MAPK) in lung tissue and specific TLR9 inhibitor pretreatment can attenuate this activation. Thus, LPS-induced mtDNA release occurs in a TLR4-dependent manner, and mtDNA causes acute lung injury and systemic inflammation in a TLR9-dependent and TLR4-independent manner. FAU - Zhang, Lemeng AU - Zhang L AD - Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha 410008, China. zlmddzyx@gmail.com. FAU - Deng, Songyun AU - Deng S AD - Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha 410008, China. dengsy2014@foxmail.com. FAU - Zhao, Shuangping AU - Zhao S AD - Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha 410008, China. zsping8888@sina.cn. FAU - Ai, Yuhang AU - Ai Y AD - Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha 410008, China. ayhicu1978@126.com. FAU - Zhang, Lina AU - Zhang L AD - Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha 410008, China. zln7095@163.com. FAU - Pan, Pinhua AU - Pan P AD - Department of Respiratory Medicines, Xiangya Hospital, Central South University, Changsha 410008, China. pinhuapan668@126.com. FAU - Su, Xiaoli AU - Su X AD - Department of Respiratory Medicines, Xiangya Hospital, Central South University, Changsha 410008, China. Suli8779@163.com. FAU - Tan, Hongyi AU - Tan H AD - Department of Respiratory Medicines, Xiangya Hospital, Central South University, Changsha 410008, China. leopard2a1980@hotmail.com. FAU - Wu, Dongdong AU - Wu D AD - Department of Respiratory Medicines, Xiangya Hospital, Central South University, Changsha 410008, China. wdd6688@126.com. LA - eng PT - Journal Article DEP - 20160830 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (DNA, Mitochondrial) RN - 0 (HMGB1 Protein) RN - 0 (HMGB1 protein, mouse) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 0 (Tlr4 protein, mouse) RN - 0 (Tlr9 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - 0 (Toll-Like Receptor 9) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Acute Lung Injury/etiology/*metabolism MH - Animals MH - DNA, Mitochondrial/administration & dosage/*metabolism/pharmacology MH - HMGB1 Protein/genetics/metabolism MH - Injections, Intraperitoneal MH - Interleukin-1beta/genetics/metabolism MH - Interleukin-6/genetics/metabolism MH - Lipopolysaccharides/toxicity MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Sepsis/etiology/*metabolism MH - Toll-Like Receptor 4/genetics/metabolism MH - Toll-Like Receptor 9/genetics/*metabolism MH - p38 Mitogen-Activated Protein Kinases/genetics/metabolism PMC - PMC5037704 OTO - NOTNLM OT - acute lung injury OT - lipopolysaccharide OT - mitochondrial DNA OT - systemic inflammation COIS- The authors declare no conflict of interest. EDAT- 2016/09/03 06:00 MHDA- 2017/03/24 06:00 PMCR- 2016/09/01 CRDT- 2016/09/03 06:00 PHST- 2016/07/04 00:00 [received] PHST- 2016/08/08 00:00 [revised] PHST- 2016/08/23 00:00 [accepted] PHST- 2016/09/03 06:00 [entrez] PHST- 2016/09/03 06:00 [pubmed] PHST- 2017/03/24 06:00 [medline] PHST- 2016/09/01 00:00 [pmc-release] AID - ijms17091425 [pii] AID - ijms-17-01425 [pii] AID - 10.3390/ijms17091425 [doi] PST - epublish SO - Int J Mol Sci. 2016 Aug 30;17(9):1425. doi: 10.3390/ijms17091425.