Original pre-clinical science
Inhibition of renin angiotensin aldosterone system causes abrogation of obliterative airways disease through inhibition of tumor necrosis factor-α–dependant interleukin-17

https://doi.org/10.1016/j.healun.2011.12.012Get rights and content

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.

Section snippets

Materials and methods

All experiments in this study were performed in compliance with the guidelines of the Institutional Laboratory Animal Care and Use Committee of Washington University School of Medicine (protocol 20070121).

ACEI and ARB abrogate the development of OAD lesions after administration of antibodies to MHC class I

To determine the role of alloimmunity in development of OAD, we previously developed a murine model for OAD. At 30 days after intrabronchial administration of anti-MHC class I antibody (anti–H-2Kb), classic OAD lesions developed in the lungs of C57Bl/6 mice, as evidenced by the cardinal features, namely, cellular infiltration around the vessels, bronchioles, epithelial hyperplasia, and fibrosis. However, similar administration of C1.18.4 control antibody of the same isotype in the control

Discussion

Although the pathogenesis of BOS is not fully defined, several risk factors have been associated with the development of chronic rejection, including acute rejection, cytomegalovirus, gastroesophageal reflux disease, and HLA mismatches.20 Previous studies from our laboratory and others have proposed a role for antibodies to self-antigens collagen V and K-α1T in the pathogenesis of BOS after LTx.9, 19, 21 Alloimmune-mediated development of de novo autoimmunity to self-antigens appears to have a

Disclosure statement

This work was supported by National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI)/National Institute of Allergy and Infectious Diseases (NIAID) grant HL092514−01A2 and the BJC Foundation to T.M. and NIH/NHLBI grant T32 HL007312 to J.W.

The authors thank Billie Glasscock for her help in preparing this manuscript.

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts

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  • Cited by (0)

    JW and VT are the co-first authors of this manuscript.

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