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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.

SUBMITTER: Dupuis J

PROVIDER: S-EPMC7710059 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Colchicine reduces lung injury in experimental acute respiratory distress syndrome.

Dupuis Jocelyn J Sirois Martin G MG Rhéaume Eric E Nguyen Quang T QT Clavet-Lanthier Marie-Élaine MÉ Brand Genevieve G Mihalache-Avram Teodora T Théberge-Julien Gabriel G Charpentier Daniel D Rhainds David D Neagoe Paul-Eduard PE Tardif Jean-Claude JC

PloS one 20201202 12

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 ...[more]

PMID: 33264297

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Project description:BACKGROUND:Acute kidney injury (AKI) is the most frequent extra-pulmonary organ failure in acute respiratory distress syndrome (ARDS). The objective of this study was to assess the factors associated with the development and severity of AKI in patients with ARDS. METHODS:This is a retrospective cohort study of ARDS patients without acute or chronic kidney disease prior to the onset of ARDS over a 7-year period (2010-2017). AKI and severity of AKI were defined according to the Kidney Disease Improving Global Outcomes 2012 guidelines. RESULTS:Of the 634 ARDS patients, 357 patients met study criteria. A total of 244 (68.3%) patients developed AKI after ARDS onset: 60 (24.6%) had stage I AKI, 66 (27%) had stage II AKI, and 118 (48.4%) had stage III AKI. The median time of AKI onset for stage I AKI was 2 days (interquartile range, 1.5-5.5) while stage II and III AKI was 4 days. On multivariable analysis, factors associated with development of AKI were age [subdistribution hazard ratio (SHR) 1.01, 95% confidence interval (CI) 1.00-1.02], SOFA score (SHR 1.16, 95%CI 1.12-1.21), a history of diabetes mellitus (DM) (SHR 1.42, 95%CI 1.07-1.89), and arterial pH on day 1 of ARDS (SHR per 0.1 units decrease was 1.18, 95%CI 1.05-1.32). In severity of AKI, stage I AKI was associated with age (SHR 1.03, 95%CI 1.01-1.05) and serum bicarbonate on day 1 of ARDS (SHR 1.07, 95%CI 1.02-1.13). Stage II AKI was associated with age (SHR 1.03, 95%CI 1.01-1.05), serum bicarbonate on day 1 (SHR 1.12, 95%CI 1.06-1.18), SOFA score (SHR 1.19, 95%CI 1.10-1.30), history of heart failure (SHR 3.71, 95%CI 1.63-8.46), and peak airway pressure (SHR 1.04, 95%CI 1.00-1.07). Stage III AKI was associated with a higher BMI (SHR 1.02, 95%CI 1.00-1.03), a history of DM (SHR 1.79, 95%CI 1.18-2.72), SOFA score (SHR 1.29, 95%CI 1.22-1.36), and arterial pH on day 1 (SHR per 0.1 units decrease was 1.25, 95%CI 1.05-1.49). CONCLUSIONS:Age, a higher severity of illness, a history of diabetes, and acidosis were associated with development of AKI in ARDS patients. Severity of AKI was further associated with BMI, history of heart failure, and peak airway pressure.

Project description:BackgroundFibroproliferative repair starts early in the inflammatory phase of acute respiratory distress syndrome (ARDS) and indicates a poor prognosis. Lumican, a small leucine-rich proteoglycan, is implicated in homeostasis and fibrogenesis, but its role in ARDS is unclear.MethodsBronchoalveolar lavage fluid (BALF) samples were obtained from ARDS patients (n = 55) enrolled within 24 h of diagnosis and mechanically ventilated (n = 20) and spontaneously breathing (n = 29) control subjects. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse models were intratracheally administered an adeno-associated virus (AAV) vector expressing lumican shRNA. Primary human lung fibroblasts (HLF) and small airway epithelial cells (SAECs) were cultured with tumour necrosis factor (TNF)-α or lumican. Luminex/ELISA, histochemistry/immunohistochemistry, immunofluorescence microscopy, quantitative real-time PCR, and western blotting were performed.ResultsLumican levels were significantly higher in the BALF of ARDS patients than in that of ventilated or spontaneously breathing controls (both p < 0.0001); they were correlated with the PaO2/FiO2 ratio and levels of proinflammatory cytokines (interleukin-6, interleukin-8, and TNF-α) and profibrotic factors (fibronectin, alpha-1 type I collagen [COL1A1], and alpha-1 type III collagen [COL3A1]). Lumican expression was enhanced in the alveolar walls and airway epithelium in the ALI mouse model. Murine lumican levels were also linked to proinflammatory and profibrotic cytokine levels in the BALF. In vitro, TNF-α induced the synthesis and secretion of lumican in HLF. In turn, lumican increased the expression of alpha-smooth muscle actin (α-SMA), COL1A1, and COL3A1 in HLF, upregulated α-SMA and COL3A1, downregulated E-cadherin, and caused spindle-shaped morphological changes in SAECs. Moreover, increased ERK phosphorylation and Slug were noted in both HLF and SAECs treated with lumican. In vivo, AAV-mediated knockdown of lumican inhibited the pulmonary production of fibronectin and COL3A1 and alleviated lung fibrotic lesions in LPS-challenged mice.ConclusionsPulmonary lumican levels were increased early in human and experimental ARDS and linked to disease severity and inflammatory fibrotic processes. Lumican triggers the transdifferentiation of lung fibroblasts into myofibroblasts and epithelial-mesenchymal transition in SAECs, possibly via the ERK/Slug pathway. Knockdown of pulmonary lumican attenuated extracellular matrix deposition in ALI mice. Overall, lumican promotes fibrotic responses in the early phase of ARDS, suggesting its potential as a therapeutic target.

Project description:ObjectiveThe Lung Injury Prediction Score identifies patients at risk for acute respiratory distress syndrome in the emergency department, but it has not been validated in non-emergency department hospitalized patients. We aimed to evaluate whether Lung Injury Prediction Score identifies non-emergency department hospitalized patients at risk of developing acute respiratory distress syndrome at the time of critical care contact.DesignRetrospective study.SettingFive academic medical centers.PatientsNine hundred consecutive patients (≥ 18 yr old) with at least one acute respiratory distress syndrome risk factor at the time of critical care contact.InterventionsNone.Measurements and main resultsLung Injury Prediction Score was calculated using the worst values within the 12 hours before initial critical care contact. Patients with acute respiratory distress syndrome at the time of initial contact were excluded. Acute respiratory distress syndrome developed in 124 patients (13.7%) a median of 2 days (interquartile range, 2-3) after critical care contact. Hospital mortality was 22% and was significantly higher in acute respiratory distress syndrome than non-acute respiratory distress syndrome patients (48% vs 18%; p < 0.001). Increasing Lung Injury Prediction Score was significantly associated with development of acute respiratory distress syndrome (odds ratio, 1.31; 95% CI, 1.21-1.42) and the composite outcome of acute respiratory distress syndrome or death (odds ratio, 1.26; 95% CI, 1.18-1.34). A Lung Injury Prediction Score greater than or equal to 4 was associated with the development of acute respiratory distress syndrome (odds ratio, 4.17; 95% CI, 2.26-7.72), composite outcome of acute respiratory distress syndrome or death (odds ratio, 2.43; 95% CI, 1.68-3.49), and acute respiratory distress syndrome after accounting for the competing risk of death (hazard ratio, 3.71; 95% CI, 2.05-6.72). For acute respiratory distress syndrome development, the Lung Injury Prediction Score has an area under the receiver operating characteristic curve of 0.70 and a Lung Injury Prediction Score greater than or equal to 4 has 90% sensitivity (misses only 10% of acute respiratory distress syndrome cases), 31% specificity, 17% positive predictive value, and 95% negative predictive value.ConclusionsIn a cohort of non-emergency department hospitalized patients, the Lung Injury Prediction Score and Lung Injury Prediction Score greater than or equal to 4 can identify patients at increased risk of acute respiratory distress syndrome and/or death at the time of critical care contact but it does not perform as well as in the original emergency department cohort.

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Colchicine reduces lung injury in experimental acute respiratory distress syndrome.

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Colchicine reduces lung injury in experimental acute respiratory distress syndrome.

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