Repeated LPS Exposure Augments Alloimmune-Dependent and Airway-Targeted Chronic Lung Allograft Fibrosis in a Mouse Model

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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