PURPOSE: Transglutaminase-2 (TG-2), the most ubiquitous member of transglutaminase, has been reported to play an important role in the process of inflammation. However, the studies about the TG-2 in lung injury are very sparse. The purpose of this study is to investigate the role of TG-2 in the pathogenesis of ventilator-associated lung injury (VALI).
METHODS: Specific pathogen-free, 5 weeks of age, male C57BL/6 mice were used. VALI was induced by mechanical ventilation (tidal volume 35 mL/Kg + respiratory rate 90/min + PEEP 0 cmH2O + 4 hours) after lipopolysaccharide (LPS, 0.5mg/Kg/50uL i.t.) instillation. The mice were experimented divide into four groups (n=6 in each group): control, VALI, VALI+Cyst (VALI + cystamine, TG-2 inhibitor, 200 mg/Kg i.p.), and LPV (lung protective ventilation, tidal volume 7 mL/Kg + respiratory rate 90/min + PEEP 3 cmH2O + 4 hours) groups. TG-2 activities were measured in the lung tissue homogenates using fluorescence based protein and expressed as relative fluorescence unit (RFU). Inflammatory cytokines, nuclear factor-kB (NF-kB) activity, and myeloperoxidase (MPO) were determined.
RESULTS: The TG-2 activities in the control, VALI, VALI+Cyst, and LPV groups were 657.34 ± 37.71 RFU, 1,087.67 ± 37.31 RFU, 721.24 ± 49.07 RFU and 889.45 ± 45.25, respectively (p=0.002 by Kruskal-Wallis test), in which the VALI+Cyst group showed significantly lower TG-2 activity than the VALI group (p=0.012). Tumor necrosis factor-a, interleukin (IL)-1b, and IL-6 concentrations were significantly lower in the VALI+Cyst group than the VALI group (p<0.05). NF-kB activity and MPO of the VALI+Cyst group were also decreased than the VALI group (p<0.05)
CONCLUSIONS: TG-2 activity was increased in VALI. The treatment with TG-2 inhibitor decreased the TG-2 activity, along with inflammatory cytokines, NF-kB activity and MPO.
CLINICAL IMPLICATIONS: These results suggest the potential role of TG-2 in the pathogenesis of VALI and TG-2 inhibitor in the treatment of acute lung injury and acute respiratory distress syndrome.
DISCLOSURE: The following authors have nothing to disclose: Je Hyeong Kim, Dae Wui Yoon, Se Joong Kim, In Bum Suh, Eun Joo Lee, Gyu Young Hur, Sung Yong Lee, Sang Yeub Lee, Chol Shin, Jae Jeong Shim, Kwang Ho In, Kyung Ho Kang, Se Hwa Yoo
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