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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Respiratory Research 1/2018

Inhibition of histone-deacetylase activity rescues inflammatory cystic fibrosis lung disease by modulating innate and adaptive immune responses

Respiratory Research > Ausgabe 1/2018
Manish Bodas, Steven Mazur, Taehong Min, Neeraj Vij
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Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12931-017-0705-8) contains supplementary material, which is available to authorized users.



Chronic lung disease resulting from dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) and NFκB-mediated neutrophilic-inflammation forms the basis of CF-related mortality. Here we aimed to evaluate if HDAC inhibition controls Pseudomonas-aeruginosa-lipopolysaccharide (Pa-LPS) induced airway inflammation and CF-lung disease.


For in vitro experiments, HEK293-cells were transfected with IL-8 or NFκB-firefly luciferase, and SV40-renilla- luciferase reporter constructs or ΔF508-CFTR-pCEP, followed by treatment with suberoylanilide hydroxamic acid (SAHA), Trichostatin-A (TSA) and/or TNFα. For murine studies, Cftr +/+ or Cftr −/− mice (n = 3) were injected/instilled with Pa-LPS and/or treated with SAHA or vehicle control. The progression of lung disease was monitored by quantifying changes in inflammatory markers (NFκB), cytokines (IL-6/IL-10), neutrophil activity (MPO, myeloperoxidase and/or NIMP-R14) and T-reg numbers.


SAHA treatment significantly (p < 0.05) suppresses TNFα-induced NFκB and IL-8 reporter activities in HEK293-cells. Moreover, SAHA, Tubacin (selective HDAC6-inhibitor) or HDAC6-shRNAs controls CSE-induced ER-stress activities (p < 0.05). In addition, SAHA restores trafficking of misfolded-ΔF508-CFTR, by inducing protein levels of both B and C forms of CFTR. Murine studies using Cftr +/+ or Cftr −/− mice verified that SAHA controls Pa-LPS induced IL-6 levels, and neutrophil (MPO levels and/or NIMP-R14), NFκB-(inflammation) and Nrf2 (oxidative-stress marker) activities, while promoting FoxP3+ T-reg activity.


In summary, SAHA-mediated HDAC inhibition modulates innate and adaptive immune responses involved in pathogenesis and progression of inflammatory CF-lung disease.
Additional file 1: Figure S1. Selective HDAC inhibition controls ER-stress activity. (A) HEK293 cells were transiently transfected with two different HDAC6 shRNA constructs or control plasmid and the cell lysates were immunoblotted for HDAC6 and β-actin. The immunoblot verifies the >2 fold knockdown efficiency of HDACshRNA for experiment shown in B. (B) HEK293 cells were transiently transfected with a secretory gaussia reporter plasmid and/or HDAC6 shRNA. After 6 h of transfection cells were treated with CSE (cigarette smoke extract, as ER stress activator), SAHA (10 μM), or Tubacin (10 μM) after 6 h. At 72 (B, upper panel) or 24 (B, lower panel) hours, supernatants were collected and read with the aforementioned Dual Luciferase Reporter System to determine ER-stress activity. The data (mean ± SD of triplicate samples) shows that CSE induced ER-stress activity (p < 0.05) is significantly controlled by Class II HDAC inhibitor, (SAHA), selective HDAC6 inhibitor (Tubacin, B-upper panel) and HDAC6 shRNA (B-lower panel) suggesting the therapeutic potential of selective HDACi in controlling CF-related ER-stress response. (C) The Cftr +/+ mice were exposed to sub-chronic cigarette smoke (sc-CS, 8 weeks) and i.t. instilled with SAHA (50 μg/mouse, three total doses with one day interval before the termination of the experiment). The BALF cells were harvested and analyzed for CD4+ (CD4-PE antibody) and FoxP3+ [(FoxP3 (Rabbit polyclonal primary Ab)-Anti-Rabbit-FITC (secondary Ab)] cells by flow cytometry using the BD FACS Caliber instrument. The data indicates that SAHA treatment induces the levels of FoxP3+ T regs to counteract the sc-CS mediated airway inflammation. (JPEG 259 kb)
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