TIPE2 ameliorates lipopolysaccharide-induced apoptosis and inflammation in acute lung injury
Tumour necrosis factor-α-induced protein 8-like 2 (TIPE2) has strong anti-inflammatory properties. However, it is unknown whether increased TIPE2 is protective against lipopolysaccharide (LPS)-induced ALI. In the current study, we aimed to investigate whether increased TIPE2 can exert protective effects in a mouse model of ALI induced by LPS.
We administered TIPE2 adeno-associated virus (AAV-TIPE2) intratracheally into the lungs of mice. Three weeks later, ALI was induced by intratracheal injection of LPS into BALB/c mice. Twenty-four hours later, lung bronchoalveolar lavage fluid (BALF) was acquired to analyse cells and protein, arterial blood was collected for arterial blood gas analysis and the determination of pro-inflammatory factor levels, and lung issues were collected for histologic examination, transmission electron microscopy (TEM), TUNEL staining, wet/dry (W/D) weight ratio analysis, myeloperoxidase (MPO) activity analysis and blot analysis of protein expression.
We found that TIPE2 overexpression markedly mitigated LPS-induced lung injury, which was evaluated by the deterioration of histopathology, histologic scores, the W/D weight ratio, and total protein expression in the BALF. Moreover, TIPE2 overexpression markedly attenuated lung inflammation, as evidenced by the downregulation of polymorphonuclear neutrophils (PMNs) in the BALF, lung MPO activity, and pro-inflammatory cytokine levels in the serum. Moreover, TIPE2 overexpression not only dramatically prevented LPS-induced pulmonary cell apoptosis in mice but also blocked LPS-activated JNK phosphorylation and NF-κB p65 nuclear translocation.
Our study shows that the increased expression of AAV-mediated TIPE2 in the lungs of mice inhibits acute inflammation and apoptosis and suppresses the activation of NF-κB and JNK in a murine model of ALI.
KeywordsAcute lung injury TIPE2 Apoptosis Inflammation Cytokines NF-κB JNK
Acute lung injury
Acute respiratory distress syndrome
Bronchoalveolar lavage fluid
Enzyme-linked immunosorbent assay
Deoxynucleotidyl transferase dUTP nick end labeling
Tumor necrosis factor-α-induced protein 8-like 2
This work was supported by research grants from the National Natural Science Foundation of China (no. 81571941).
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 5.Zgraggen BR, Tornic J, Müller-Edenborn B, Reyes L, Booy C, Beck-Schimmer B. Acute lung injury: apoptosis in effector and target cells of the upper and lower airway compartment. Clin Exp Immunol. 2010;161(2):324–31.Google Scholar
- 8.Boonstra A, Rajsbaum R, Holman M, Marques R, Asselin-Paturel C, Pereira JP, et al. Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and TRIF-dependent TLR signals, and TLR-independent signals. J Immunol. 2006;177(11):7551–8.CrossRefGoogle Scholar
- 12.Xu L, Yu J, Zhai DX, Zhang DY, Shen W, Bai LL, et al. Role of JNK activation and mitochondrial Bax translocation in allicin-induced apoptosis in human ovarian cancer SKOV3 cells. Evid Based Complement Alternat Med. 2014;2014:378684.Google Scholar
- 16.Li B, Zeng M, He W, Huang X, Luo L, Zhang H, et al. Ghrelin protects alveolar macrophages against lipopolysaccharide-induced apoptosis through growth hormone secretagogue receptor 1a-dependent c-Jun N-terminal kinase and Wnt/beta-catenin signaling and suppresses lung inflammation. Endocrinology. 2015;156(1):203–17.CrossRefGoogle Scholar
- 23.Kumar D, Whiteside TL, Kasid U. Identification of a novel tumor necrosis factor-alpha-inducible gene, SCC-S2, containing the consensus sequence of a death effector domain of fas-associated death domain-like interleukin- 1beta-converting enzyme-inhibitory protein. J Biol Chem. 2000;275(4):2973–8.CrossRefGoogle Scholar
- 24.Wang H, Wang L, Li N, Li J, Yu F, Zhao Y, et al. Subanesthetic isoflurane reduces zymosan-induced inflammation in murine kupffer cells by inhibiting ROS-activated p38 MAPK/NF-κB signaling. Oxid Med Cell Longev. 2014;2014:851692.Google Scholar
- 27.Blackwell TS, Blackwell TR, Holden EP, Christman BW, Christman JW. In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation. J Immunol. 1996;157(4):1630–7.Google Scholar
- 31.Kumar D, Whiteside TL, Kasid U. Identification of a novel tumor necrosis factor-alpha-inducible gene, SCC-S2, containing the consensus sequence of a death effector domain of fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein. J Biol Chem. 2000;275:2973–8.CrossRefGoogle Scholar