DNase to the Rescue! Clearing Mitochondrial DNA May Have NET Benefits in Lung Transplantation
Bibliographic record
Abstract
DNase to the Rescue! Clearing Mitochondrial DNA May Have NET Benefits in Lung TransplantationSurvival after lung transplant is inferior compared with that after other solid organ transplants, owing to the constant exposure of the lung to the environment and the rich immune milieu within the allograft.Innate immune stimuli trigger injury in transplanted lungs, increasing the risk of acute and chronic lung allograft dysfunction.Pattern recognition receptors (PRRs), which protect the host against infection by binding to pathogen-associated molecular patterns, are instrumental in activating innate immunity.PRRs are also triggered by damage-associated molecular patterns (DAMPs), which are released during sterile tissue injury, including ischemia-reperfusion injury (IRI) (1).The first study that reported a role for PRRs in lung transplant showed that recipient Toll-like receptor (TLR) 4 loss-of-function polymorphisms correlated with lower rates of acute rejection (2).Endotoxin-driven TLR4 signaling plays a role in murine models of alloimmune lung injury and inflammation (3, 4).In addition, pulmonary DAMPs, such as HMGB1 (high mobility group protein B1), heat shock proteins, hyaluronan, tenascin C, and nucleic acids, including mitochondrial DNA (mtDNA), augment rejection or fibrosis in murine models and have been associated with acute and chronic rejection in human lung transplant recipients (1).We believe that the earliest events in the life of the pulmonary allograft are critical determinants of long-term outcome.Primary graft dysfunction (PGD), the clinical correlate of IRI, is an important risk factor for chronic lung allograft dysfunction in humans (5, 6).In addition, IRI augments chronic rejection in a mouse orthotopic lung transplant model ( 7).The assumption is that DAMPs, released during IRI, increase T-cell priming (8), thus augmenting acute rejection and potentiating injurious and profibrotic pathways.However, the specific DAMPs involved and their downstream mechanisms in lung PGD are unclear.In this issue of the Journal, Mallavia and colleagues (pp.364-372) report on the role of mtDNA in driving TLR9-mediated neutrophil extracellular trap (NET) formation in a mouse model of PGD (9).Their group had previously demonstrated NET accumulation in experimental and human PGD and showed that NET eradication with intrabronchial deoxyribonuclease (DNase) I in mice improved graft function (10).The mechanisms of NET production, however, remained obscure.Using a syngeneic mouse orthotopic lung transplant model, Mallavia and colleagues now show (9) that mtDNA is elevated in the BAL after prolonged lung allograft cold ischemia compared with minimal ischemia.Importantly, purified mtDNA is sufficient to release NETs and recapitulate PGD after minimal ischemia.Supporting the potential clinical relevance of these findings, the authors demonstrate higher levels of mtDNA and NETs in the BAL of patients with severe PGD than in patients with no or minimal PGD.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
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".