Abstract
BackgroundIn acute respiratory distress syndrome (ARDS), uncontrolled production of activators of coagulation and proinflammatory mediators results in a shift from an adequate local innate immune response to hypercoagulability and inflammation. This study aimed to investigate whether the protease inhibitors antithrombin (AT) and alpha-1 protease inhibitor (A1PI) may attenuate an exaggerated pulmonary immune response.MethodsLung injury was induced either by single intranasal administration of lipopolysaccharide (LPS) (5 mg/kg) in BALB/c mice or by combination of an intravenous injection of LPS (10 mg/kg) with subsequent injurious ventilation using high tidal volumes (12–15 ml/kg) for 4 h in RccHan Wistar rats. Animals received either a single bolus of AT (250 IU/kg) or A1PI (60 mg/kg) alone or in combination, with or without intravenous low-dose heparin (100 U/kg). Control animals received saline. Additional controls received neither LPS, nor ventilation, nor treatment. Endpoints were local and systemic markers of coagulation, e.g., thrombin–antithrombin complexes (TATc), and inflammation, e.g., interleukin-6.ResultsBoth lung injury models resulted in a pronounced immune response within the pulmonary compartment shown by elevated levels of markers of coagulation and inflammation. The two-hit lung injury model also induced profound systemic coagulopathy and inflammation. Monotherapy with AT or A1PI did not reduce pulmonary coagulopathy or inflammation in any lung injury model. Nor did combination therapy with AT and A1PI result in a decrease of coagulation or inflammatory parameters. AT markedly reduced systemic levels of TATc in the two-hit lung injury model. Systemic inflammation was not affected by the different interventions. Additional administration of heparin did not lead to macroscopic bleeding incidences.ConclusionsIn two different murine models of acute lung injury, neither single therapy with AT or A1PI nor combination of both agents attenuates the pronounced pulmonary coagulation or inflammatory response.
Highlights
In acute respiratory distress syndrome (ARDS), uncontrolled production of activators of coagulation and proinflammatory mediators results in a shift from an adequate local innate immune response to hypercoagulability and inflammation
ARDS is a heterogeneous syndrome characterized by local production of coagulation proteases and proinflammatory mediators causing a shift from a potentially adequate innate immune response to harmful coagulation and inflammation [1, 2]
Antithrombin (AT) and alpha-1 protease inhibitor (A1PI) are serine protease inhibitors playing a pivotal role in maintaining equilibrium between protective and harmful coagulation and inflammation [6,7,8]
Summary
In acute respiratory distress syndrome (ARDS), uncontrolled production of activators of coagulation and proinflammatory mediators results in a shift from an adequate local innate immune response to hypercoagulability and inflammation. ARDS is a heterogeneous syndrome characterized by local production of coagulation proteases and proinflammatory mediators causing a shift from a potentially adequate innate immune response to harmful coagulation and inflammation [1, 2]. A1PI is an acute-phase protein exerting anti-inflammatory effects by blocking proteolytic enzymes released by activated neutrophils into the pulmonary compartment, acting as an “anti-protease screen” [7]. Both AT and A1PI were administered in an indirect ARDS model in sheep leading to attenuation of microvascular protein permeability within the lungs and prevention of a decrease in arterial oxygenation. None of these effects were observed when only one intervention was administered [12]
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