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. 2020 Nov 22:2020:6705985.
doi: 10.1155/2020/6705985. eCollection 2020.

Lipoxin A4 Reduces Ventilator-Induced Lung Injury in Rats with Large-Volume Mechanical Ventilation

Qi Wang  1 , Guang-Xiao Xu  1 , Qi-Hang Tai  1 , Yan Wang  1
Affiliations

Lipoxin A4 Reduces Ventilator-Induced Lung Injury in Rats with Large-Volume Mechanical Ventilation

Qi Wang et al. Mediators Inflamm. .

Abstract

Ventilator-induced lung injury (VILI) is a severe and inevitable complication in patients who require mechanical ventilation (MV) for respiratory support. Lipoxin A4 is an endogenous anti-inflammatory and antioxidant mediator. The present study determined the effects of lipoxin A4 on VILI. Twenty-four rats were randomized to the sham, VILI, and lipoxin A4 (LX4) groups. The rats in the VILI and LX4 groups received large-volume MV for 4 hours to simulate VILI. Capillary permeability was evaluated using the PaO2/FiO2 ratio, lung wet/dry weight ratio, and protein level in the lung. VILI-induced inflammation was assessed by measuring cytokines in serum and lung tissue, the expression and activity of NF-κB, and phosphorylated myosin light chain. The oxidative stress response, lung tissue injury, and apoptosis in lung tissue were also estimated, and the expression of apoptotic proteins was examined. MV worsened all of the indices compared to the sham group. Compared to the VILI group, the LX4 group showed significantly improved alveolar-capillary permeability (increased PaO2/FiO2 and decreased wet/dry weight ratios and protein levels), ameliorated histological injury, and reduced local and systemic inflammation (downregulated proinflammatory factors and NF-κB expression and activity). Lipoxin A4 notably inhibited the oxidative stress response and apoptosis and balanced apoptotic protein levels in lung tissue. Lipoxin A4 protects against VILI via anti-inflammatory, antioxidant, and antiapoptotic effects.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Lipoxin A4 improved alveolar-capillary permeability in VILI. Compared to the sham group, the PaO2/FiO2 was decreased, and the wet/dry weight ratio and protein levels in BALF were increased in the VILI and LX4 groups. Compared to the VILI group, the PaO2/FiO2 was increased (a), and the wet/dry weight ratio (b) and protein concentration (c) were decreased by lipoxin A4. ∗P < 0.05, vs. the sham group; #P < 0.05, vs. the VILI group. ●: sham group; ■: VILI group; ▲: LX4 group.
Figure 2
Figure 2
Lipoxin A4 reduced the histological injury score in VILI. After 4 hours of large-volume MV, many inflammatory cells infiltrated into lung tissue, and the alveolar wall was thickened and broken. There was severe mesenchymal oedema and haemorrhage in the lung tissue in the VILI group (a). Compared to the VILI group, the histological score in the LX4 group was significantly decreased. The histological injury score is presented in (b). ∗P < 0.05, vs. the sham group; #P < 0.05, vs. the VILI group. ●: sham group; ■: VILI group; ▲: LX4 group.
Figure 3
Figure 3
Lipoxin A4 reduced systemic inflammation in VILI. After MV, the levels of ICAM-1 and MIP-2 in serum were significantly increased in the VILI and LX4 groups. However, lipoxin A4 notably reduced the increase in ICAM-1 and MIP-2 levels in serum. ∗P < 0.05, vs. the sham group; #P < 0.05, vs. the VILI group. ●: sham group; ■: VILI group; ▲: LX4 group.
Figure 4
Figure 4
Lipoxin A4 inhibited VILI-induced local inflammation. Compared to the levels in the sham group, the levels of TNF-α, IL-1β, IL-6, and IL-10 were significantly increased in the VILI group after large-volume MV. Compared to the VILI group, TNF-α, IL-1β, and IL-6 levels were decreased, and the IL-10 level was increased in the LX4 group (a). The activity and expression of NF-κB and the expression of p-MLC were notably increased in response to MV. The upregulation of NF-κB and MLC was significantly abrogated by lipoxin A4 (b). Similar to the effect on cytokines, the increased infiltration of neutrophils and macrophages was also abrogated by lipoxin A4 (c). ∗P < 0.05, vs. the sham group; #P < 0.05, vs. the VILI group. ●: sham group; ■: VILI group; ▲: LX4 group.
Figure 5
Figure 5
Lipoxin A4 reduced the oxidative stress response after VILI. In the VILI group, the activity of NADPH and SOD and the concentrations of cGMP and MDA were promoted by large-volume MV. Compared to the VILI group, NADPH and MDA were reduced by lipoxin A4, and cGMP and SOD were increased by lipoxin A4. ∗P < 0.05, vs. the sham group; #P < 0.05, vs. the VILI group. ●: sham group; ■: VILI group; ▲: LX4 group.
Figure 6
Figure 6
Lipoxin downregulated the apoptotic index in VILI. The number of apoptotic cells in lung tissue was increased in rats that received 4 hours of MV. Cellular apoptosis was significantly lower in the LX4 group than the VILI group (a). Compared to the VILI group, the LX4 group had a notably inhibited expression of Bax and caspase-3 but increased Bcl-xL expression in lung tissue (b). ∗P < 0.05, vs. the sham group; #P < 0.05, vs. the VILI group. ●: sham group; ■: VILI group; ▲: LX4 group.
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