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. 2017 Apr 3;7(1):572.
doi: 10.1038/s41598-017-00551-8.

Protective effect of TM6 on LPS-induced acute lung injury in mice

Xiaoyu Hu  1 , Yuan Tian  1 , Shihui Qu  1 , Yongguo Cao  1 , Shumin Li  1 , Wenlong Zhang  1 , Zecai Zhang  1 , Naisheng Zhang  2 , Yunhe Fu  3
Affiliations

Protective effect of TM6 on LPS-induced acute lung injury in mice

Xiaoyu Hu et al. Sci Rep. .

Abstract

Acute lung injury (ALI) is an acute failure of the respiratory system for which effective treatment is urgently necessary. Previous studies found that several peptides potently inhibited the production of cytokines induced by lipopolysaccharide (LPS). In this study, we synthetized a cell-permeable TIR domain-derived decoy peptide (TM6) and examined its substance for the ability to inhibit TLR signaling in the model of ALI induced by LPS. We demonstrated that TM6 (2.5, 5 and 10 nmol/g) alleviated the histological changes in the lung tissues as well as myeloperoxtidase (MPO) activity, lung W/D ratio, the production of TNF-α, IL-1β and IL-6 induced by LPS. Furthermore, the numbers of total cells, neutrophils and macrophages in the BALF were suppressed by TM6. In vitro, TM6 (5, 10 and 20 µM) inhibited the production of TNF-α, IL-1β and IL-6 in LPS-stimulated alveolar macrophages. Moreover, the activation of Nuclear factor-kappaB (NF-κB) and Mitogen activated protein kinases (MAPK) signaling pathways induced by LPS were also inhibited by TM6. Collectively, our results suggested that TM6 was an effective inhibitor of ALI induced by LPS, and this peptide may very well serve as a future treatment for ALI.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
The effect of TM6 on lung tissue histopathological changes. Histopathologic sections of lung tissues (H and E, ×100). (A) Lung tissues from control, (B) LPS, (C) LPS + TM6 (2.5 nmol/g), (D) LPS + TM6 (5 nmol/g), (E) LPS + TM6 (10 nmol/g), and (F) LPS + DEX (5 mg/kg) mice, (G) the pathological scores was evaluate during ALI.
Figure 2
Figure 2
The effect of TM6 on lung wet/dry radio. Mice were pretreated with TM6 (2.5, 5 and 10 nmol/g) and DEX (5 mg/kg) 1 h prior to an i.n. administration of LPS. The lung wet/dry ratio was determined 7 h after LPS challenge. The values presented are the means ± SEM (n = 6). #P < 0.01 is significantly different from the control group; *P < 0.05 and **P < 0.01 are significantly different from the LPS group.
Figure 3
Figure 3
The effects of TM6 on the number of total cells, neutrophils, and macrophages in the BALF. Mice were given an intraperitoneal injection of TM6 (2.5, 5 and 10 nmol/g) and DEX (5 mg/kg) 1 h prior to an i.n. administration of LPS. BALF was collected 7 h after LPS administration to measure the number of total cells (a), neutrophils (b), and macrophages (c). The values presented are the means ± SEM (n = 6). #P < 0.01 is significantly different from the control group; *P < 0.05 and **P < 0.01 are significantly different from the LPS group.
Figure 4
Figure 4
The effect of TM6 on cytokines production in BALF. Mice were given an intraperitoneal injection of TM6 (2.5, 5 and 10 nmol/g) and DEX (5 mg/kg) 1 h prior to an i.n. administration of LPS. BALF was collected 7 h following LPS challenge to analyze the inflammatory cytokines TNF-α, IL-1β, and IL-6. The values presented are means ± SEM (n = 6). # P < 0.01 is significantly different from the control group; * P < 0.05 and ** P < 0.01 are significantly different from the LPS group.
Figure 5
Figure 5
The effect of TM6 on MPO activity. MPO activity was determined 7 h after LPS administration. The values presented are the means ± SEM. (n = 6) # P < 0.01 is significantly different from the control group; * P < 0.05 and ** P < 0.01 are significantly different from the LPS group.
Figure 6
Figure 6
The effect of TM6 on cell viability. Alveolar macrophages extract from mice were treatment with different concentrations of TM6 (0–40 µM) in the absence or presence LPS (1 µg/ml) for 24 hours. The cells viability was tested by MTT assay. The values presented are means ± SEM (n = 6). # P < 0.01 is significantly different from the control group; * P < 0.05 and ** P < 0.01 are significantly different from the LPS group.
Figure 7
Figure 7
The effect of TM6 on inflammatory cytokines production in alveolar macrophages. Alveolar macrophages were treated with TM6 (5, 10 and 20 µM) and DEX (1 mM) 1 hour prior to stimulation with LPS. 24 hours later, the suspension was collected to test the levels of TNF-α, IL-1β, and IL-6. The values presented are means ± SEM (n = 6). # P < 0.01 is significantly different from the control group; * P < 0.05 and ** P < 0.01 are significantly different from the LPS group.
Figure 8
Figure 8
The effect of TM6 on NF-κB pathway. The effects of TM6 on the expression of the NF-κB pathway that was induced by LPS. Alveolar macrophages were pretreated with TM6 (5, 10 and 20 µM) for 1 hour and then treated with LPS for 1 hour. NF-κB protein samples were analyzed by western blot with specific antibodies. β-actin was used as a control. The values presented are the means ± SEM of three independent experiments, # P < 0.01 is significantly different from the control group; * P < 0.05 and ** P < 0.01 are significantly different from the LPS group.
Figure 9
Figure 9
The effect of TM6 on MAPK pathway. Alveolar macrophages were pretreated with TM6 (5, 10 and 20 µM) for 1 hour and then treated with LPS for 1 hour. MAPK protein samples were analyzed by western blot with specific antibodies. β-actin was used as a control. The values presented are the means ± SEM of three independent experiments, # P < 0.01 is significantly different from the control group; * P < 0.05 and ** P < 0.01 are significantly different from the LPS group.
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