Pulmonary Coagulopathy as a New Target in Lung Injury - A Review of Available Pre-Clinical Models

Abstract

Despite recent advances in supportive care, acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are clinical entities with high morbidity and high mortality. In systemic inflammation, like sepsis, uncontrolled host defense can lead to systemic activation of coagulation on the one hand, and attenuation of fibrinolysis on the other. In ALI/ARDS similar but local disturbances in fibrin turnover occur, leading to excessive alveolar fibrin deposition compromising pulmonary integrity and function. Therapies in patients with sepsis have specifically focused on coagulation disturbances. Evidence from preclinical and clinical investigations suggests pharmacologically targeting pulmonary "coagulopathy" could be of benefit to patients with ALI/ARDS as well. Recent animal studies have demonstrated that administration of heparins, activated protein C (APC), Antithrombin (AT), Tissue factor-Factor VIIa (TF-FVIIa) pathway inhibitors, plasminogen activators (PA) and thrombomodulin (TM) can attenuate pulmonary coagulopathy and reduce lung injury and/or improve oxygenation. Some of these studies have also shown anti-inflammatory effects of treatment targeting at coagulation. To date there are no published studies that have specifically studied the effects of anticoagulants on ALI/ARDS however there are on-going clinical trials. A solid base has to be provided by preclinical studies to justify clinical studies on new pharmacologic therapies for ALI/ARDS. In this systematic literature review we give an overview of the models for ALI/ARDS that have been used so far on the topic of pulmonary coagulopathy and focus on the pharmacological interventions that have been evaluated with these models. Finally, the applicability of the different approaches for future research on this subject will be discussed.

Ruscogenin inhibits lipopolysaccharide-induced acute lung injury in mice: Involvement of tissue factor, inducible NO synthase and nuclear factor (NF)-κB

“…Accumulating evidence from preclinical and clinical investigations indicates that sepsis and ALI marked by TF-dependent activation of coagulation lead to the formation of thrombin and subsequent deposition of fibrin. Inhibition in pulmonary "coagulopathy" could be of benefit to patients with ALI/ARDS as well [26]. We then observed the effect of ruscogenin on TF expression in the lung tissue in this model.…”

Direct Hemoperfusion Using Immobilized Polymyxin B in Patients with Rapidly Progressive Interstitial Pneumonias: A Retrospective Study

“…The prednisolone dosage was tapered after high-dose corticosteroid pulse therapy, and immunosuppressants were also prescribed for some patients. Several reports have indicated that antioxidant therapy, such as N-acetylcysteine [23,24,25] or anticoagulation therapy [26,27,28], is useful for ALI/ARDS; however, none of the study patients received antioxidant or anticoagulation therapy.…”

Therapeutic Modulation of Coagulation and Fibrinolysis in Acute Lung Injury and the Acute Respiratory Distress Syndrome

“…Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are devastating illnesses marked by diffuse lung inflammation and increased vascular permeability resulting in endothelial and epithelial injury, pulmonary edema and organ dysfunction [1-4]. These syndromes result from either a direct lung injury (pneumonia, aspiration of gastric contents or inhalation injury) or from a systemic insult (sepsis, hemorrhagic shock, severe trauma, transfusion of blood products) [1].…”

“…These syndromes result from either a direct lung injury (pneumonia, aspiration of gastric contents or inhalation injury) or from a systemic insult (sepsis, hemorrhagic shock, severe trauma, transfusion of blood products) [1]. The current therapeutic strategy to decrease ALI/ARDS-associated mortality is to utilize protective mechanical ventilation with a plateau pressure-limited low tidal volume strategy [2].…”

“…However, despite some improvement with this intervention, both morbidity and mortality remain high with mortality rates from ALI/ARDS exceeding 30% [3]. Although mechanical ventilation is a necessary and life-saving measure in patients with ARDS, mechanical ventilation itself may potentiate or aggravate lung injury and inflammation, referred to as ventilator-induced lung injury (VILI) [1]. Therefore, given the continued high mortality, development of new therapies for both prevention and treatment of lung injury continues to be the focus of ALI/ARDS research [4-6].…”