Colchicine reduces lung injury in experimental acute respiratory distress syndrome

Abstract

The acute respiratory distress syndrome (ARDS) is characterized by intense dysregulated inflammation leading to acute lung injury (ALI) and respiratory failure. There are no effective pharmacologic therapies for ARDS. Colchicine is a low-cost, widely available drug, effective in the treatment of inflammatory conditions. We studied the effects of colchicine pre-treatment on oleic acid-induced ARDS in rats. Rats were treated with colchicine (1 mg/kg) or placebo for three days prior to intravenous oleic acid-induced ALI (150 mg/kg). Four hours later they were studied and compared to a sham group. Colchicine reduced the area of histological lung injury by 61%, reduced lung edema, and markedly improved oxygenation by increasing PaO2/FiO2 from 66 ± 13 mmHg (mean ± SEM) to 246 ± 45 mmHg compared to 380 ± 18 mmHg in sham animals. Colchicine also reduced PaCO2 and respiratory acidosis. Lung neutrophil recruitment, assessed by myeloperoxidase immunostaining, was greatly increased after injury from 1.16 ± 0.19% to 8.86 ± 0.66% and significantly reduced by colchicine to 5.95 ± 1.13%. Increased lung NETosis was also reduced by therapy. Circulating leukocytosis after ALI was not reduced by colchicine therapy, but neutrophils reactivity and CD4 and CD8 cell surface expression on lymphocyte populations were restored. Colchicine reduces ALI and respiratory failure in experimental ARDS in relation with reduced lung neutrophil recruitment and reduced circulating leukocyte activation. This study supports the clinical development of colchicine for the prevention of ARDS in conditions causing ALI.

Fig 1. Effects of colchicine therapy on oleic acid-induced ALI, lung edema and gas exchange.

Values are mean ± SEM. **** p<0.0001; *** p<0.001, ** p<0.01; * p<0.05.

Fig 2. Effects of colchicine therapy on lung injury, neutrophils recruitment, and NETosis after oleic acid-induced ALI.

Values are mean ± SEM. **** p<0.0001; *** p<0.001, ** p<0.01; * p<0.05.

Fig 3. Effects of colchicine therapy on plasma cytokines and NETs 4 hours after oleic acid ALI.

Values are mean ± SEM. **** p<0.0001; *** p<0.001, ** p<0.01; * p<0.05.

Fig 4. Whole blood flow cytometry analysis of leukocytes after oleic acid-induced ALI and effects of colchicine therapy.

MFI, mean fluorescence intensity. Values are mean ± SEM. *** p<0.001, ** p<0.01; * p<0.05.

Fig 5. Clustered heatmap representation of unsupervised clustering of lung tissue mRNA expression of 27 selected markers of inflammation and injury.