The Role of TGF-β in the Association Between Primary Graft Dysfunction and Bronchiolitis Obliterans Syndrome

Abstract

Primary graft dysfunction (PGD) is a possible risk factor for bronchiolitis obliterans syndrome (BOS) following lung transplantation; however, the mechanism for any such association is poorly understood. Based on TGF-β's association with acute and chronic inflammatory disorders, we hypothesized that it may play a role in the continuum between PGD and BOS. Thus, the association between PGD and BOS was assessed in a single-center cohort of lung transplant recipients. Bronchoalveolar lavage fluid concentrations of TGF-β and procollagen collected within 24 hours of transplantation were compared across the spectrum of PGD, and incorporated into Cox models of BOS. Immunohistochemistry localized expression of TGF-β and its receptor in early lung biopsies post-transplant. We found an association between PGD and BOS in both bilateral and single lung recipients with a hazard ratio of 3.07 (95% CI 1.76-5.38) for the most severe form of PGD. TGF-β and procollagen concentrations were elevated during PGD (p<0.01), and associated with increased rates of BOS. Expression of TGF-β and its receptor localized to allograft infiltrating mononuclear and stromal cells, and the airway epithelium. These findings validate the association between PGD and the subsequent development of BOS, and suggest that this association may be mediated by receptor/TGF-β biology.

Absence of evidence that respiratory viral infections influence pediatric lung transplantation outcomes: Results of the CTOTC-03 study

“…[41][42][43] We found that identification of common respiratory viruses in NP or BAL specimens was not predictive of poor outcome as measured by a composite endpoint of death, retransplant, or development of CLAD based on OB and BOS criteria. 3 In contrast to adult LTRs, ACR and PGD were not related to the development of BOS/OB or the composite endpoint.…”

“…3 In contrast to adult LTRs, ACR and PGD were not related to the development of BOS/OB or the composite endpoint. [41][42][43] We found that identification of common respiratory viruses in NP or BAL specimens was not predictive of poor outcome as measured by a composite endpoint of death, retransplant, or development of CLAD based on OB and BOS criteria. Although subjects with a CARV identified in NP or BAL were less likely to meet the composite endpoint, particularly when the CARV was associated with symptoms, this could be due to a competing risk bias in that subjects with good outcomes had more follow-up time to develop more viral infections.…”

Lung transplant after prolonged ex vivo lung perfusion: predictors of allograft function in swine

“…On the one hand, it is conceivable that all injured lungs stabilize their perfusion and ventilation characteristics by 24 h but that the level of peak injury at 8 h is most predictive of their ultimate performance. This is akin to the phenomenon of ‘transient primary graft dysfunction’ whereby transient acute lung injury that resolves still has lasting effect on the allograft after transplant .…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…With the emergence of molecular imaging, new sensitive and selective imaging probes have been developed that can be translated from animal models to patients. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging can detect and monitor a variety of pathophysiological processes such as T cell activity by glucose uptake and neutrophil activation by binding of the peptide cinnamoyl-F-(D)L-F-(D)L-F (cFLFLF) to the formyl peptide receptor 1 (FPR1) (48)(49)(50). Multiphoton intravital microscopy can also be used to assess specific cell populations and functions during murine IRI (51)(52)(53).…”