Search

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., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: Alana Sampson, Brittany Lassiter, Pamela Hair, Adrianne Enos, Kenji Cunnion and Neel Krishna are employees of ReAlta Life Sciences. Neel Krishna and Kenji Cunnion have ownership of ReAlta shares and Kenji Cunnion serves as on the Board of Directors of ReAlta Life Sciences. Neel K Krishna and Kenji M Cunnion are listed as inventors on patents that describe PIC1 molecules. The authors would like to declare the following patents/patent applications associated with this research: 8,241,843 methods for regulating complement cascade proteins using astrovirus coat protein and derivatives thereof, 15/738,786 synthetic peptide compounds and methods of use, 16/400,486 synthetic peptide compounds and methods of use, 8,906,845 peptide compounds to regulate the complement system, 9,422,337 peptide compounds to regulate the complement system, 10,005,818 derivative peptide compounds and methods of use, 9,914,753 peptide compounds to regulate the complement system, 10,414,799 peptide compounds to regulate the complement system, 16/534,200 peptide compounds to regulate the complement system, 16/242,550 PIC1 inhibition of myeloperoxidase oxidative activity in an animal model. The commercial affiliation with ReAlta Life Sciences does not alter our adherence to PLOS ONE policies on sharing data and materials.