Peptide inhibition of acute lung injury in a novel two-hit rat model

PLoS One. 2021 Oct 28;16(10):e0259133. doi: 10.1371/journal.pone.0259133. eCollection 2021.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / drug therapy*
  • Acute Lung Injury / pathology
  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / therapeutic use*
  • Complement Activation / drug effects*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Erythrocyte Transfusion
  • Humans
  • Lipopolysaccharides
  • Lung / drug effects*
  • Lung / pathology
  • Male
  • Neutrophil Infiltration / drug effects*
  • Rats
  • Rats, Wistar

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • Lipopolysaccharides

Grants and funding

This work was funded by ReAlta Life Sciences, Inc, an entity that is pursuing therapeutic development of the Peptide Inhibitors of Complement C1 (EPICC molecules) for various clinical applications. https://realtalifesciences.com/. ACS, BPL, PSH, AIE, KMC and NKK receive salary from ReAlta. Other than the named authors, no other members of ReAlta as the funding entity participated in study design, data collection and analysis, the decision to publish or the preparation of the manuscript. The funder provided support in the form of salaries for authors ACS, BPL, PSH, AIE, KMC and NKK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.