Selected article for: "chronic lung allograft dysfunction and lung allograft"

Author: Wheeler, David S; Misumi, Keizo; Walker, Natalie M; Vittal, Ragini; Combs, Michael P; Aoki, Yoshiro; Braeuer, Russell R; Lama, Vibha N
Title: Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis.
  • Cord-id: xhjkpg32
  • Document date: 2020_11_29
  • ID: xhjkpg32
    Snippet: Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently show 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 2-fold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels comp
    Document: Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently show 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 2-fold 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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