期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 21, 期 7, 页码 2360-2371出版社
WILEY
DOI: 10.1111/ajt.16417
关键词
animal models; murine; basic (laboratory) research; science; bronchiolitis obliterans (BOS); cellular biology; cytokines; cytokine receptors; fibrosis; lung transplantation; pulmonology; translational research; science
资金
- National Heart, Lung, and Blood Institute [HL007749-26, HL094622, HL118017]
- Brian and Mary Campbell and Elizabeth Campbell-Carr research gift fund
- Cystic Fibrosis Foundation [LAMA16XX0]
Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction consistently shows both mononuclear cell inflammation and mesenchymal cell fibroproliferation, with interleukin 6 (IL-6) potentially playing a critical role in mediating the communication between these cells and contributing to the pathogenesis of CLAD.
Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL-6) trans-signaling may be a critical mediator of MNC-MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels compared to matched pre-CLAD samples. Human BAL-derived MCs do not respond to treatment with IL-6 alone but have rapid and prolonged JAK2-mediated STAT3 Tyr705 phosphorylation when exposed to the combination of IL-6 and sIL-6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL-6 and sIL-6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL-6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL-6 and sIL-6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.
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