title: Inhibition of renin angiotensin aldosterone system causes abrogation of obliterative airways disease through inhibition of tumor necrosis factor-α-dependant interleukin-17.
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-α-dependant IL-6 through p38/MAPKinase pathway and thus abrogation of anti-MHC-induced OAD.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Weber
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
authors.forename: Masashi
authors.initials: M
authors.lastname: Takenaka
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Ramsey
authors.initials: R
authors.lastname: Hachem
authors.forename: Elbert
authors.initials: E
authors.lastname: Trulock
authors.forename: G Alec
authors.initials: GA
authors.lastname: Patterson
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000009:adverse effects / Q000276:immunology; D001989:Bronchiolitis Obliterans / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D015536:Down-Regulation; D020381:Interleukin-17 / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology; D008285:Major Histocompatibility Complex / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000502:physiology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000906:Antibodies; D020381:Interleukin-17; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases