Antimicrobial peptides CATH‐2 and LL‐37 produce no protective effect after intratracheal co‐administration with LPS in vivo
Bibliographic record
Abstract
Background The host inflammatory response produced in bacterial pneumonia is a major contributing factor of the pathophysiologic processes observed in a respiratory infection. Antimicrobial peptides (AMPs) have been shown to possess potent broad‐spectrum antimicrobial activity as well as immunomodulatory properties. As a potential therapy for bacterial pneumonia, we have previously investigated the anti‐bacterial properties of AMPs in the presence of a pulmonary delivery agent, exogenous surfactant. To further explore the properties of these compounds, the current study evaluates the effects of AMPs with and without exogenous surfactant on pulmonary inflammation in vivo . Objective The objective of this study was to investigate the potential of two cathelicidin peptides, CATH‐2 and LL‐37 and the exogenous surfactant/cathelicidin mixture BLES+CATH‐2, to reduce the inflammatory response produced upon LPS stimulation in vivo . Hypothesis Intrapulmonary administration of AMPs, with and without exogenous surfactant, will reduce lipopolysaccharide (LPS) induced inflammation. Methods Two cathelicidin peptides, CATH‐2 and LL‐37, were used in this study. CATH‐2 was also administered in combination with bovine lipid‐extract surfactant (BLES), as previous studies have shown bactericidal activity and enhanced biophysical function of this combination in vitro . C57Bl/6 mice were anesthetized, intubated, and intratracheally instilled 2 mg/kg of LPS. Five minutes later, mice were intratracheally instilled with 50μL one of the following treatments: Sham (no LPS), Air, Saline, BLES (20 mg phospholipid/kg BW), CATH‐2 (100 μM), LL‐37 (100 μM), or BLES+CATH‐2. The mice were monitored for six hours, and were then euthanized. A FlexiVent was used to measure lung compliance, and bronchoalveolar lavage (BAL) fluid was collected in order to determine cell counts, cell differentials, protein content and inflammatory cytokine concentrations. Results Animals that were administered LPS showed a significant increase in neutrophil recruitment and lavage IL‐6 content compared to sham control. Animals treated with CATH‐2 and LL‐37 showed a significant decrease in lung compliance compared to all other treatment groups, as well as an increase in lavage protein and IL‐6 content obtained from the BAL fluid. There was no significant difference among treatment groups with respect to total cells found in the BAL fluid, or percentage of neutrophils recovered between treatment groups. Discussion The results from this experiment did not support our initial hypothesis, as CATH‐2 and LL‐37 did not reduce the inflammatory response elicited by LPS challenge, but instead produced an exacerbated inflammatory response as well as decreased lung function, as observed through a decrease in lung compliance. It is possible that at the doses utilized, the cytotoxic effects of cathelicidins contributed to the inflammatory responses observed. The addition of exogenous surfactant BLES mitigated the deleterious effects of CATH‐2 administration; however it did not affect the markers of inflammation compared to controls. Support or Funding Information Canadian Institutes of Health Research Program of Experimental Medicine Cystic Fibrosis Foundation
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".