Inhibition of renin angiotensin aldosterone system causes abrogation of obliterative airways disease through inhibition of tumor necrosis factor-αdependant interleukin-17

Joseph Weber, Venkataswarup Tiriveedhi, Masashi Takenaka, Wei Lu, Ramsey Hachem, Elbert Trulock, G. Alec Patterson, T. Mohanakumar

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Background: Alloimmune-induced immune responses to self-antigens are involved in the development of chronic lung allograft rejection. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been shown to modulate autoimmune diseases. This study investigated the effect of modulation of the renin angiotensin aldosterone system (RAAS) a murine model of obliterative airways disease (OAD). Methods: Major histocompatibility complex (MHC) class I antibodies were administered intrabronchially to C57Bl/6 mice on Days 1, 2, 3, and 6, and weekly thereafter. ACEI/ARB (10 mg/kg/day) were administered in water 5 days before antibody administration. Antibodies were analyzed by enzyme-linked immunosorbent assay, cytokines by Luminex, Th-frequency by enzyme-linked immunosorbent spot, and transcription factors by Western blotting and real-time polymerase chain reaction. Results: Significant decreases (50%70%) in airway lesions and fibrous deposition were noted in lungs at Day 30 in the animals administered ACEI and ARB vs controls. Antibody concentrations to self-antigens also decreased from 14 ± 21 to 62 ± 18 μg/ml for collagen V and from 263 ± 43 to 84 ± 28 μg/ml for K-α1 tubulin. Th-precursor frequency and cytokine analysis showed increased interleukin (IL)-10 (3-fold increase) and decreased levels of IL-6 (3.4-fold) and IL-17 (4-fold decrease; p < 0.05) in ACEI and ARB groups. There was also messenger RNA level downregulation of tumor necrosis factor-α (8.6-fold) and p38/mitogen-activated protein (MAP)kinase (3.1-fold) in the treatment groups. Conclusions: Our results demonstrate that modulation of RAAS leads to downregulation of IL-17 through tumor necrosis factor-αdependant IL-6 through p38/MAPKinase pathway and thus abrogation of anti-MHCinduced OAD.

Original languageEnglish
Pages (from-to)419-426
Number of pages8
JournalJournal of Heart and Lung Transplantation
Volume31
Issue number4
DOIs
StatePublished - Apr 1 2012

Keywords

  • ACE inhibitors
  • TH-17 pathway
  • TNF-alpha
  • obliterative airway disease
  • renin angiotensis aldosterone system

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