Role of P2X Receptors on Endothelial Cell Injury Mediated by Complement Activation
Bibliographic record
Abstract
Background: The complement system is critical for to innate immunity. The complement system consists of over 50 proteins, provides defense against microbes, mediates inflammatory responses. The final step of complement activation is formation of the membrane attack complex (MAC, C5b-9). Complement over-activation is implicated in the pathophysiology of numerous diseases, yet the mechanisms underlying host cell damage are not fully elucidated. The P2X receptors, are transmembrane cationic channels gated by adenosine triphosphate (ATP) which are present in the plasma membrane (PM) of most excitable and non-excitable cells including all segments of the nephron, and renal cells. Recently, a link between complement system and P2X receptors has been established, showing that inhibition of P2X activation decreases complement mediated cell damage. The aim of this study is to determine the role of P2X receptors activity in complement activation on primary endothelial cells. Methods: Complement was activated on blood outgrowth endothelial cells (BOECs) using an established protocol, first sensitizing the cells using a specific antibody to CD59, followed by treatment with normal human serum. Complement activity was assessed by measuring the deposition of C3b and C5b-9 on BOEC PM via immunofluorescence using specific antibodies. Intracellular Ca2+ levels were measured using a fluorescent calcium indicator (Invitrogen). ATP release was measured using a commercial ATP luminescence assay (Promega). Results: Complement activation caused C3b and C5b-9 deposition on the PM of BOECs, followed by Ca2+ influx and ATP release. Cells treated with P2X receptor antagonists, showed a significant decrease in C5b-9 deposition compared to untreated controls. In addition, P2X antagonist treatment significantly ameliorated Ca2+ influx as well as ATP release. Conclusions: The finding of reduced C5b-9 deposition on BOECs in the presence of P2X receptor antagonists suggests an important functional link between the complement system and purinergic system. While more research is required to fully elucidate the interactions between these critical, ubiquitous biological systems, our results contribute to a better understanding of the consequences of complement activation on endothelial cells and suggest new therapeutic targets for disease related to dysregulated complement system. Funding: Commercial Support - Paragon Ventures Inc, Vancouver, BC, Canada
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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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".