Abstract
Acute lung injury (ALI) often causes severe trauma that may progress to significant morbidity and mortality. ALI results from a combination of the underlying clinical condition of the patient (e.g., inflammation) with a secondary insult such as viral pneumonia or a blood transfusion. While the secondary insult may be variable, the rapidly progressive disease process leading to pulmonary failure is typically mediated by an overwhelming innate immunological or inflammatory reaction driven by excessive complement and neutrophil-mediated inflammatory responses. We recently developed a ‘two-hit’ ALI rat model mediated by lipopolysaccharide followed by transfusion of incompatible human erythrocytes resulting in complement activation, neutrophil-mediated ALI and free DNA in the blood indicative of neutrophil extracellular trap formation. The objective of this study was to evaluate the role of peptide inhibitor of complement C1 (RLS-0071), a classical complement pathway inhibitor and neutrophil modulator in this animal model. Adolescent male Wistar rats were infused with lipopolysaccharide followed by transfusion of incompatible erythrocytes in the presence or absence of RLS-0071. Blood was collected at various time points to assess complement C5a levels, free DNA and cytokines in isolated plasma. Four hours following erythrocyte transfusion, lung tissue was recovered and assayed for ALI by histology. Compared to animals not receiving RLS-0071, lungs of animals treated with a single dose of RLS-0071 showed significant reduction in ALI as well as reduced levels of C5a, free DNA and inflammatory cytokines in the blood. These results demonstrate that RLS-0071 can modulate neutrophil-mediated ALI in this novel rat model.
Highlights
Acute lung injury (ALI) is often a complication of severe trauma that can progress to acute respiratory distress syndrome (ARDS) resulting in significant morbidity and mortality [1]
While the secondary insult may differ, the rapidly progressive disease process leading to pulmonary failure is typically mediated by an exaggerated and overwhelming innate immunological or inflammatory response driven by excessive complement and neutrophil-mediated inflammatory responses
In the case of TRALI, which represents one of the leading causes of transfusion-related mortality, this disease process is complex and not fully understood, a ‘two-hit’ model is currently believed to most accurately exemplify the clinical situation with the first hit mediated by the underlying clinical condition of the patient and the second hit triggered by a component in the transfused unit [10, 11]
Summary
Acute lung injury (ALI) is often a complication of severe trauma that can progress to acute respiratory distress syndrome (ARDS) resulting in significant morbidity and mortality [1]. In the case of TRALI, which represents one of the leading causes of transfusion-related mortality, this disease process is complex and not fully understood, a ‘two-hit’ model is currently believed to most accurately exemplify the clinical situation with the first hit mediated by the underlying clinical condition of the patient and the second hit triggered by a component in the transfused unit [10, 11]. In vivo and ex vivo studies have implicated neutrophils as a key player in the pathogenesis of TRALI through direct activation, formation of reactive oxygen species (ROS) and neutrophil extracellular trap (NET) formation resulting in acute lung injury (ALI) [12]. It has previously been postulated that the complement system may play a role in TRALI through C3a and C5a interaction with neutrophils resulting in neutrophil activation as well as ROS and NET formation [13], studies showing such a direct connection have to date been lacking
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