Abstract and Introduction
Abstract
Introduction Diabetic patients may develop acute lung injury less often than non-diabetics; a fact that could be partially ascribed to the usage of antidiabetic drugs, including metformin. Metformin exhibits pleiotropic properties which make it potentially beneficial against lung injury. We hypothesized that pretreatment with metformin preserves alveolar capillary permeability and, thus, prevents ventilator-induced lung injury.
Methods Twenty-four rabbits were randomly assigned to pretreatment with metformin (250 mg/Kg body weight/day per os) or no medication for two days. Explanted lungs were perfused at constant flow rate (300 mL/min) and ventilated with injurious (peak airway pressure 23 cmH2O, tidal volume ≈17 mL/Kg) or protective (peak airway pressure 11 cmH2O, tidal volume ≈7 mL/Kg) settings for 1 hour. Alveolar capillary permeability was assessed by ultrafiltration coefficient, total protein concentration in bronchoalveolar lavage fluid (BALF) and angiotensin-converting enzyme (ACE) activity in BALF.
Results High-pressure ventilation of the ex-vivo lung preparation resulted in increased microvascular permeability, edema formation and microhemorrhage compared to protective ventilation. Compared to no medication, pretreatment with metformin was associated with a 2.9-fold reduction in ultrafiltration coefficient, a 2.5-fold reduction in pulmonary edema formation, lower protein concentration in BALF, lower ACE activity in BALF, and fewer histological lesions upon challenge of the lung preparation with injurious ventilation. In contrast, no differences regarding pulmonary artery pressure and BALF total cell number were noted. Administration of metformin did not impact on outcomes of lungs subjected to protective ventilation.
Conclusions Pretreatment with metformin preserves alveolar capillary permeability and, thus, decreases the severity of ventilator-induced lung injury in this model.
Introduction
Despite its firmly established role as a fundamental life-support modality for critically ill patients, mechanical ventilation (MV) may elicit ventilator-induced lung injury (VILI), which is characterized by alveolar edema and hemorrhage. Recognized mechanisms of VILI include alveolar over-distention by high tidal volumes (volutrauma) and cyclic opening and closing of alveoli (atelectrauma), which operate in concert to trigger inflammatory processes (biotrauma), oxidant/antioxidant imbalance, intra-alveolar coagulation and disturbances in surfactant function.
Clarification of the above pathophysiologic mechanisms serves a basis for the discovery of effective pharmacological therapies against VILI, which currently is mainly prevented through the limitation of the mechanical insult to the lung parenchyma (that is, through the implementation of protective ventilation). Such pharmacological therapies could be novel agents, for example, sphingosine 1-phosphate, or drugs already in clinical use. Our research group contributed to the idea that established drugs may indeed be beneficial when they are re-used for indications other than their initial indication, a concept which we call the drug recycle concept; indeed, we reported that pretreatment with atorvastatin attenuates VILI. Reduced cost, clinician familiarity and known undesired effects profile are obvious advantages of using drugs with proven efficacy for a different indication.
Such a popular established drug is metformin (N',N'-dimethylbiguanide), which enjoys a long-standing recognition in the setting of type 2 diabetes mellitus. Metformin recently emerged as a potential adjunct in the management of patients with cancer; a fact indicating that it may also have effects other than its antihyperglycemic ones. Indeed, there is growing (albeit still limited) evidence that metformin might exhibit pleiotropic properties, including anti-angiogenic, anti-inflammatory, antioxidant and endothelial barrier-enhancing. Some of the above properties might make metformin a potential candidate for protection against VILI as well.
Interestingly, several clinical studies point out that diabetic patients develop acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) less frequently than non-diabetics; a benefit that could be partially ascribed to the usage of antidiabetic therapies, such as metformin. This evidence (derived from observational studies) along with the known pleiotropic effects of metformin (derived from experimental studies) generated the research idea that it could indeed prevent lung injury. Thus, we endeavored to test the hypothesis that pretreatment with metformin preserves pulmonary vascular permeability, and therefore, confers protection against VILI in non-diabetic animals.