[Therapeutic effects of histone deacetylase inhibitor givinostat on air inflammation and high airway resistance in a murine asthma model].
Objective:To investigate the therapeutic effects of givinostat, a histone deacetylase inhibitor (HDACI), on the development of chronic asthma with airway inflammation, airway remodeling and airway hyperresponsiveness (AHR).Methods:BALB/C mice were randomly divided into control group, asthma group, dexamethasone group and givinostat group (n=12 per group). AHR was assessed. Total cell numbers and differential counts, interleukin-4(IL-4), interleukin-5(IL-5) and interferon-γ (IFNγ) levels in the bronchoalveolar lavage fluid (BALF) were measured in the above 4 groups. The pathology of lung tissue was evaluated. Immunohistochemical (IHC) staining and Western blot were used to detect α smooth muscle actin(α-SMA) and transforming growth factor-β1(TGFβ1).Results:Compared with the asthma only group, givinostat treatment relieved airway resistance (2.96±1.01 vs 6.50±0.79,P<0.05). Total inflammatory cells [(33.04±5.62)×10(4)/ml vs (98.04±9.27)×10(4)/ml,P<0.01], eosinophil cells [(9.17±2.33)×10(4)/ml vs(37.64±6.98)×10(4)/ml,P<0.01], IL-4 [(10.12±2.98)ng/ml vs (16.88±2.78)ng/ml,P<0.05] and IL-5 [(27.09±3.62)ng/ml vs (37.86±7.34)ng/ml,P<0.05] levels were all reduced in givinostat group, while IFNγ [(91.86±23.73)pg/ml vs (60.49±11.88)pg/ml,P>0.05] was enhanced in BALF. Inflammatory cell infiltration around the airway was reduced, with decreased inflammatory cell score[(1.60±0.69)points vs (3.40±0.68) points,P<0.01] and inflammatory cell number (111.65±31.41 vs 601.25±186.85,P<0.01). The goblet cell metaplasia [(26.36±2.33)% vs (57.21±11.56)%] and collagen deposition area [(52.77±7.58)μm(2)/μm vs (111.81±12.40)μm(2)/μm] were obviously reduced (P<0.01). The expressions of α-SMA and TGFβ1 in the lung tissue were both significantly decreased (P<0.01).Conclusion:Givinostat treatment can reduce airway inflammation, airway remodeling and airway hyperresponsiveness in chronic asthma. Its effect is comparable to that of glucocorticoid hormone treatment.
Institute of Respiratory Disease, the First Affiliated Hospital of China Medical University, Shenyang 110001, China.
X M
XM
Su
Y
Y
Ren
L F
LF
Kong
J
J
Kang
D056151:Airway Remodeling / Q000187:drug effects*; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation; D007371:Interferon-gamma; D015847:Interleukin-4 / Q000032:analysis; D015848:Interleukin-5; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011897:Random Allocation; D053773:Transforming Growth Factor beta1
D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D002219:Carbamates; D056572:Histone Deacetylase Inhibitors; C508598:IL4 protein, human; C508599:IL5 protein, human; D015848:Interleukin-5; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4; C575255:givinostat; D007371:Interferon-gamma
Airway resistance; Asthma; Histone deacetylase inhibitor; Inflammation