Innate Immune Responses in Obliterative Bronchiolitis After Lung Transplantation - The Role of Statins and Hypoxia-Inducible Factor-1
Year: 2015
Type: dissertation
Abstract: Chronic lung allograft dysfunction (CLAD) is the major life-limiting factor after lung transplantation and bronchiolitis obliterans syndrome (BOS) is the most common subtype and best-characterized form of CLAD. Pathologically, BOS presents as obliterative bronchiolitis (OB) and it is characterized by peribronchial inflammation, epithelial damage, and obliteration of small and medium-sized bronchioli by fibrotic plaques. BOS is the leading cause mortality after the first post-operative year. In this study, we hypothesized that inhibiting innate immune activation through different pathways influences the development of experimental OB. To test our hypothesis, we investigated different factors and pathways leading to experimental OB using both rat and mouse heterotopic tracheal allograft models. In the presence of alloantigens, early ischemic injury induced both innate and adaptive immune responses followed by Th17 activation and afterwards by a sustained Th1 immune response. This was accompanied by infiltration of the allograft with proinflammatory effector cells and lead to progressive fibroproliferation and total tracheal occlusion. Interestingly, recipient treatment with simvastatin, a cholesterol-lowering drug with lipid-independent immunomodulatory properties, enhanced early epithelial recovery after transplantation in the allografts. It also inhibited the infiltration of inflammatory cells and the expression of lymphocyte chemokines and proinflammatory cytokine mRNA. Most importantly, simvastatin inhibited the development of experimental OB in the absence of other immunosuppression. The cellular responses to hypoxia are regulated by transcription factors called hypoxia inducible factors (HIFs). HIF-1 is a principle regulator of hypoxic adaptation. In this study, we found that continuous HIF-1 expression in myeloid cells improved epithelial recovery, reduced inflammatory cell accumulation, and increased regulatory FoxP3 mRNA expression in mouse tracheal allografts. Importantly, these effects led to better preservation of tracheal epithelium and a decrease in the development of experimental OB suggesting a protective role of HIF-1 in this constellation.
Source: Työväentutkimus Vuosikirja
Author: Jussi Ropponen
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1928452710