Repeated LPS Exposure Augments Alloimmune-Dependent and Airway-Targeted Chronic Lung Allograft Fibrosis in a Mouse Model
Bibliographic record
Abstract
Purpose: Outcomes after lung transplantation are poor in comparison with those of other solid organs mainly due to chronic lung allograft dysfunction (CLAD)[1], whose pathological correlates include airway and parenchymal fibrosis[2]. Because the lung allograft is constantly exposed to the external environment, CLAD is believed to result from a complex interplay of inflammatory, infectious and alloimmune factors[3]. Hence, experimental models based solely on alloimmunity may not simulate all relevant features of CLAD. We hypothesized that repeated administration of lipopolysaccharide (LPS) would augment alloimmunity and trigger chronic rejection and fibrosis in a mouse minor alloantigen-mismatched orthotopic lung transplant (OLT) model (C57BL/10 [B10, H-2b] → C57BL/6 [B6, H-2b]). Methods: Three groups of mice underwent syngeneic OLT (SynOLT: B6 → B6) or allogeneic OLT (AlloOLT: B10 → B6). Each group was given or not given 6 or 8 doses of intratracheal LPS (5 μg in 50 μl PBS) on serial postoperative days (POD). Our 3 experimental groups are as follows: Group A underwent AlloOLT with LPS, Group B underwent AlloOLT without LPS, Group C underwent SynOLT with LPS. The grafts were histologically assessed 28 days after OLT in a blinded fashion. CT scans were performed on POD 7 and 27. Results: LPS-treated mice showed bilateral lung infiltration on CT at POD 7. CT on POD 27 showed increased graft density in Group A. This change was not observed in Group B or Group C. Histological assessment of acute cellular rejection according to ISHLT criteria was as follows: Group A (score: 2.9), Group B (score: 1.7), Group C (score: 0.5) [Figure 1]. Parenchymal fibrosis was minimal in all groups. On the other hand, obliterative bronchiolitis, an important pathology seen in patients with CLAD, was found only in Group A (6 out of 10) [Figure 2 a-c. Masson trichrome stain. a: Group A, arrow indicates obliterated airway. b: Group B. c: Group C]. The right lungs of mice showed no rejection, inflammation, or airway obliteration on POD 28 [Figure 2d. HE stain of the right lung of Group A]. Conclusion: Repeated intratracheal LPS exposure augments the alloimmune response and causes airway-dominant CLAD-like pathology in a minor alloantigen-mismatched mouse OLT model. These findings reveal an important pathway linking environmental exposure to lung allograft rejection that may allow discovery of new therapeutic targets in CLAD.FigureFigureReferences: 1. Yusen RD. The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Lung and Heart-Lung Transplantation Report–2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant. 2015;34:1264-1277. 2. Sato M. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011;30:735-742. 3. Hsiao HM. Mechanisms of graft rejection after lung transplantation. Curr Opin Organ Transplant. 2017;22:29-35.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".