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Background
Acute respiratory distress syndrome (ARDS) is a common and devastating illness characterized by lung inflammation, endothelial and epithelial injury, increased vascular permeability and oedema; all of these factors lead to organ dysfunction. ARDS results from a direct injury such as a pneumonia or aspiration of gastric contents or from a systemic injury such as sepsis or severe trauma [1-4].
Current therapeutic strategy to decrease ARDS-associated mortality is to utilize protective mechanical ventilation in combination with low tidal volume. However, morbidity and mortality remain high, both exceeding 40% [5-7]. The need for new specific pharmacological therapies has carried to examine the role of altered coagulation and fibrinolysis in the pathogenesis of ARDS.
Pulmonary coagulopathy is intrinsic to ARDS and directly dependent on the severity of acute lung injury (ALI) and linked to the outcome of ARDS. This disease is characterized by the coagulation cascade activation and reduced fibrinolysis that leads to fibrin deposition in the airspaces and triggers inflammation. All of this occurs because of the alveolar type II cell damage and also the pro-inflammatory activation of macrophages.
In recent years, several preclinical studies have supported the use of nebulized or systemic anticoagulants to prevent and treat ALI in diverse animal models [8, 9]. Moreover, numerous clinical trials were performed with patients with ARDS or sepsis requiring unfractionated heparin (UFH), although results have been conflicting. High dose of nebulized heparin decreased pulmonary coagulation in the lung of patients with ARDS without causing systemic bleedings [10]. Furthermore, patients treated with nebulized heparin were ventilated with lower tidal volumes compared to control patients during the first 7 days of ventilation; determining an improvement in the lung function that was associated with the dosage and the days that the nebulized heparin was administered. However the administration of heparin was ineffective in the improvement of patient’s outcomes such as the survival at day 28 [11-15]. Moreover, nebulized heparin combined with N-acetylcysteine for burn inhalation injury decreased lung injury scores and the duration of mechanical ventilation. Besides, heparin was tested as a treatment in other lung diseases such as cystic fibrosis with favourable results [16].
Cellular and molecular mechanisms that control intra-alveolar fibrin deposition are not completely understood. The modulation of fibrin deposition, coagulation and fibrinolysis could be important targets...