Therapeutic Targeting of High-Mobility Group Box-1 in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
To the Editor:The importance of the immune system in pulmonary arterial hypertension (PAH) pathogenesis is increasingly recognized by clinicians and scientists (1).Immune cells are recruited to the lungs of patients with PAH (2), and preclinical studies have demonstrated their requirement for disease progression (3).The importance of the human immune system in PAH pathogenesis is underscored by our recent finding that mice, which do not develop robust experimental pulmonary hypertension, are rendered susceptible to severe disease when reconstituted with human immune tissue (4).Consequently, several clinical trials are investigating immunomodulation as PAH treatment (1).The ubiquitously expressed damage-associated molecular pattern HMGB1 (high-mobility group box-1) is gaining recognition as a mediator of PAH.HMGB1 can be secreted from immune cells in response to stress, and it mediates many paracrine and autocrine effects in inflammatory conditions (5).HMGB1, by binding TLR4 (Toll-like receptor 4), activates macrophages and lymphocytes; induces TNF (tumor necrosis factor), IL-6, and IL-1b; and triggers autoimmunity (5).All of these factors are hallmarks of PAH (1).Expression of both HMGB1 and TLR4 is elevated in lungs of patients with PAH (6), and HMGB1 is secreted in response to hypoxia (7).Conversely, mice treated with neutralizing antibodies against HMGB1 (6) or deficient in TLR4 are protected from hypoxia-induced pulmonary hypertension (8).Although targeting HMGB1/TLR4 signaling may be a promising new treatment for PAH, this strategy can be expected to come at a cost, given the multiple roles of these molecules in infection and immunity.In this study, we first consolidated the critical role of HMGB1 in PAH in human samples and animal models.Next, we tested the therapeutic efficacy of a novel peptide, P5779, which specifically targets extracellular HMGB1 in its disulfide form, disrupting its interaction with the TLR4 adaptor MD-2 (9).Hence, P5779 does not affect the epigenetic functions of intracellular HMGB1 or non-HMGB1-mediated TLR4 signaling, thus minimizing potential off-target effects of anti-HMGB1 therapies for PAH.Some of these results were previously reported in abstract form (10).
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.002 | 0.000 |
| Research integrity | 0.005 | 0.007 |
| Insufficient payload (model declined to judge) | 0.007 | 0.003 |
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".