Alpha 1-antitrypsin for treatment of ventilator-associated lung injury in acute respiratory distress syndrome rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WANG Xueting , LV Xin , GONG Jing , ZHU Jingli ,  GAO Wei

Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P. R. China;

Corresponding author：

GAO Wei, Email: gaowei20055@126.com

Keywords：

Acute lung injury; Acute respiratory distress syndrome; Alpha 1-antitrypsin; Mechanical ventilation

DOI：

10.7507/1671-6205.201904015

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Objective To estimate whether alpha 1-antitrypsin (AAT) can reduce ventilator-induced lung injury (VILI) in acute respiratory distress syndrome (ARDS) rats after mechanical ventilation.Methods The rats were randomly divided into 3 groups: a sham (S) group, a mechanical ventilation (V) group and a mechanical ventilation/AAT (VA) group. The rats in the S group only received anesthesia, and the rats in the V and VA groups received endotoxin to simulate ARDS followed by mechanical ventilation for 4 hours. At the beginning of ventilation, the rats in the V group received saline, and the rats in the VA group received AAT. The PaO₂/FiO₂ ratio and the lung wet/dry (W/D) weight ratio were tested. The total protein and neutrophil elastase concentrations and the neutrophil and macrophage counts in bronchoalveolar lavage fluid (BALF) were tested. Proinflammatory factors in BALF and intercellular cell adhesion molecule-1 (ICAM-1) and microphage inflammatoryprotein-2 (MIP-2) in the serum were also detected. Furthermore, the oxidative stress response was detected, and histological injury and apoptosis were evaluated.Results Compared with the S group, PaO₂/FiO₂ was significantly decreased in the V group and the VA group, the protein concentration in the BALF and the lung W/D weight ratio were significantly increased, the concentration of inflammatory factors in BALF and peripheral blood was significantly increased, and inflammatory cells in BALF also increased. Meanwhile, malondialdehyde (MDA) concentration, myeloperoxidase (MPO) and nicotinamide adeninedinucleotide phosphate (NADPH) activity increased significantly. The V group and VA group were severely damaged, and the number of apoptotic cells increased significantly. Compared with the V group, the PaO₂/FiO₂ in the VA group significantly increased; the W/D weight ratio and the BALF protein concentration decreased; the number of macrophages and neutrophils in the BALF, and the concentration of elastase significantly decreased; tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in BALF decreased, IL-10 increased; ICAM-1 and MIP-2 in peripheral blood decreased. At the same time, the MDA concentration, MPO and NADPH activities in the VA group were significantly lower than those in the V group; the tissue damage was significantly reduced, and the number of apoptosis was significantly reduced. In addition, compared with the V group, the expression of Bax, gelsolin and cleaved caspase-3 decreased in the VA group, but the expression of Bcl-2 was increased (all P<0.05).Conclusions AAT can relieve VILI in ARDS rats. The protection conferred by AAT may be associated with the anti-inflammatory, antioxidative stress response and antiapoptotic effect of AAT.

Citation： WANG Xueting, LV Xin, GONG Jing, ZHU Jingli, GAO Wei. Alpha 1-antitrypsin for treatment of ventilator-associated lung injury in acute respiratory distress syndrome rats. Chinese Journal of Respiratory and Critical Care Medicine, 2020, 19(1): 47-52. doi: 10.7507/1671-6205.201904015 Copy

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2.	Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med, 2013, 369(22): 2126-2136.
3.	Kotani M, Kotani T, Ishizaka A, et al. Neutrophil depletion attenuates interleukin-8 production in mild-overstretch ventilated normal rabbit lung. Crit Care Med, 2004, 32(2): 514-519.
4.	Sercundes MK, Ortolan LS, Debone D, et al. Targeting neutrophils to prevent malaria-associated acute lung injury/acute respiratory distress syndrome in mice. PLoS Pathog, 2016, 12(12): e1006054.
5.	Churg A, Dai J, Zay K, et al. Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects. Lab Invest, 2001, 81(8): 1119-1131.
6.	Lewis EC, Shapiro L, Bowers OJ, et al. α1-antitrypsin monotherapy prolongs islet allograft survival in mice. Proc Natl Acad Sci U S A, 2005, 102(34): 12153-12158.
7.	Petrache I, Fijalkowska I, Zhen L, et al. A novel antiapoptotic role for α₁-antitrypsin in the prevention of pulmonary emphysema. Am J Respir Crit Care Med, 2006, 173(11): 1222-1228.
8.	Garratt LW, Sutanto EN, Ling KM, et al. Alpha-1 antitrypsin mitigates theiInhibition of airway epithelial cell repair by neutrophil elastase. Am J Respir Cell Mol Biol, 2016, 54(3): 341-349.
9.	Petrache I, Fijalkowska I, Medler TR, et al. α-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am J Pathol, 2006, 169(4): 1155-1166.
10.	Lockett AD, Kimani S, Ddungu G, et al. α₁-Antitrypsin modulates lung endothelial cell inflammatory responses to TNF-α. Am J Respir Cell Mol Biol, 2013, 49(1): 143-150.
11.	Tan W, Zhang C, Liu J, et al. Regulatory T-cells promote pulmonary repair by modulating T helper cell immune responses in lipopolysaccharide-induced acute respiratory distress syndrome. Immunology, 2019, 157(2): 151-162.
12.	Jie Z, Cai Y, Yang W, et al. Protective effects of alpha 1-antitrypsin on acute lung injury in rabbits induced by endotoxin. Chin Med J(Engl), 2003, 116(11): 1678-1682.
13.	Halbertsma FJ, Vaneker M, Scheffer GJ, et al. Cytokines and biotrauma in ventilator-induced lung injury: a critical review of the literature. Neth J Med, 2005, 63(10): 382-392.
14.	Lomas DA, Parfrey H. α₁-antitrypsin deficiency. 4: Molecular pathophysiology. Thorax, 2004, 59(6): 529-535.
15.	Wilson MR, Choudhury S, Takata M. Pulmonary inflammation induced by high-stretch ventilation is mediated by tumor necrosis factor signaling in mice. Am J Physiol Lung Cell Mol Physiol, 2005, 288(4): L599-L607.
16.	Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest, 2000, 117(4): 1162-1172.
17.	Liu YY, Li LF, Fu JY, et al. Induced pluripotent stem cell therapy ameliorates hyperoxia-augmented ventilator-induced lung injury through suppressing the Src pathway. PLoS One, 2014, 9(10): e109953.
18.	Huang CS, Kawamura T, Lee S, et al. Hydrogen inhalation ameliorates ventilator-induced lung injury. Crit Care, 2010, 14(6): R234.
19.	Bradley PP, Priebat DA, Christensen RD, et al. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol, 1982, 78(3): 206-209.
20.	Liu KX, Wu WK, He W, et al. Ginkgo biloba extract (EGb 761) attenuates lung injury induced by intestinal ischemia/reperfusion in rats: roles of oxidative stress and nitric oxide. World J Gastroenterol, 2007, 13(2): 299-305.
21.	Zhu H, He JS, Liu J, et al. Alpha 1-antitrypsin ameliorates ventilator-induced lung injury in rats by inhibiting inflammatory responses and apoptosis. Exp Biol Med (Maywood), 2018, 243(1): 87-95.
22.	Cartron PF, Juin P, Oliver L, et al. Impact of proapoptotic proteins Bax and Bak in tumor progression and response to treatment. Expert Rev Anticancer Ther, 2003, 3(4): 563-570.

1. Force ADT, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA, 2012, 307(23): 2526-2533.
2. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med, 2013, 369(22): 2126-2136.
3. Kotani M, Kotani T, Ishizaka A, et al. Neutrophil depletion attenuates interleukin-8 production in mild-overstretch ventilated normal rabbit lung. Crit Care Med, 2004, 32(2): 514-519.
4. Sercundes MK, Ortolan LS, Debone D, et al. Targeting neutrophils to prevent malaria-associated acute lung injury/acute respiratory distress syndrome in mice. PLoS Pathog, 2016, 12(12): e1006054.
5. Churg A, Dai J, Zay K, et al. Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects. Lab Invest, 2001, 81(8): 1119-1131.
6. Lewis EC, Shapiro L, Bowers OJ, et al. α1-antitrypsin monotherapy prolongs islet allograft survival in mice. Proc Natl Acad Sci U S A, 2005, 102(34): 12153-12158.
7. Petrache I, Fijalkowska I, Zhen L, et al. A novel antiapoptotic role for α₁-antitrypsin in the prevention of pulmonary emphysema. Am J Respir Crit Care Med, 2006, 173(11): 1222-1228.
8. Garratt LW, Sutanto EN, Ling KM, et al. Alpha-1 antitrypsin mitigates theiInhibition of airway epithelial cell repair by neutrophil elastase. Am J Respir Cell Mol Biol, 2016, 54(3): 341-349.
9. Petrache I, Fijalkowska I, Medler TR, et al. α-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am J Pathol, 2006, 169(4): 1155-1166.
10. Lockett AD, Kimani S, Ddungu G, et al. α₁-Antitrypsin modulates lung endothelial cell inflammatory responses to TNF-α. Am J Respir Cell Mol Biol, 2013, 49(1): 143-150.
11. Tan W, Zhang C, Liu J, et al. Regulatory T-cells promote pulmonary repair by modulating T helper cell immune responses in lipopolysaccharide-induced acute respiratory distress syndrome. Immunology, 2019, 157(2): 151-162.
12. Jie Z, Cai Y, Yang W, et al. Protective effects of alpha 1-antitrypsin on acute lung injury in rabbits induced by endotoxin. Chin Med J(Engl), 2003, 116(11): 1678-1682.
13. Halbertsma FJ, Vaneker M, Scheffer GJ, et al. Cytokines and biotrauma in ventilator-induced lung injury: a critical review of the literature. Neth J Med, 2005, 63(10): 382-392.
14. Lomas DA, Parfrey H. α₁-antitrypsin deficiency. 4: Molecular pathophysiology. Thorax, 2004, 59(6): 529-535.
15. Wilson MR, Choudhury S, Takata M. Pulmonary inflammation induced by high-stretch ventilation is mediated by tumor necrosis factor signaling in mice. Am J Physiol Lung Cell Mol Physiol, 2005, 288(4): L599-L607.
16. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest, 2000, 117(4): 1162-1172.
17. Liu YY, Li LF, Fu JY, et al. Induced pluripotent stem cell therapy ameliorates hyperoxia-augmented ventilator-induced lung injury through suppressing the Src pathway. PLoS One, 2014, 9(10): e109953.
18. Huang CS, Kawamura T, Lee S, et al. Hydrogen inhalation ameliorates ventilator-induced lung injury. Crit Care, 2010, 14(6): R234.
19. Bradley PP, Priebat DA, Christensen RD, et al. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol, 1982, 78(3): 206-209.
20. Liu KX, Wu WK, He W, et al. Ginkgo biloba extract (EGb 761) attenuates lung injury induced by intestinal ischemia/reperfusion in rats: roles of oxidative stress and nitric oxide. World J Gastroenterol, 2007, 13(2): 299-305.
21. Zhu H, He JS, Liu J, et al. Alpha 1-antitrypsin ameliorates ventilator-induced lung injury in rats by inhibiting inflammatory responses and apoptosis. Exp Biol Med (Maywood), 2018, 243(1): 87-95.
22. Cartron PF, Juin P, Oliver L, et al. Impact of proapoptotic proteins Bax and Bak in tumor progression and response to treatment. Expert Rev Anticancer Ther, 2003, 3(4): 563-570.

Chinese Journal of Respiratory and Critical Care Medicine

Alpha 1-antitrypsin for treatment of ventilator-associated lung injury in acute respiratory distress syndrome rats

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