PMID- 22298527
OWN - NLM
STAT- MEDLINE
DCOM- 20120325
LR  - 20211021
IS  - 1535-4989 (Electronic)
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 46
IP  - 2
DP  - 2012 Feb
TI  - Trichostatin A abrogates airway constriction, but not inflammation, in murine and 
      human asthma models.
PG  - 132-8
LID - 10.1165/rcmb.2010-0276OC [doi]
AB  - Histone deacetylase (HDAC) inhibitors may offer novel approaches in the treatment 
      of asthma. We postulate that trichostatin A (TSA), a Class 1 and 2 inhibitor of 
      HDAC, inhibits airway hyperresponsiveness in antigen-challenged mice. Mice were 
      sensitized and challenged with Aspergillus fumigatus antigen (AF) and treated 
      with TSA, dexamethasone, or vehicle. Lung resistance (R(L)) and dynamic 
      compliance were measured, and bronchial alveolar lavage fluid (BALF) was analyzed 
      for numbers of leukocytes and concentrations of cytokines. Human precision-cut 
      lung slices (PCLS) were treated with TSA and their agonist-induced 
      bronchoconstriction was measured, and TSA-treated human airway smooth muscle 
      (ASM) cells were evaluated for the agonist-induced activation of Rho and 
      intracellular release of Ca(2+). The activity of HDAC in murine lungs was 
      enhanced by antigen and abrogated by TSA. TSA also inhibited methacholine 
      (Mch)-induced increases in R(L) and decreases in dynamic compliance in naive 
      control mice and in AF-sensitized and -challenged mice. Total cell counts, 
      concentrations of IL-4, and numbers of eosinophils in BALF were unchanged in mice 
      treated with TSA or vehicle, whereas dexamethasone inhibited the numbers of 
      eosinophils in BALF and concentrations of IL-4. TSA inhibited the 
      carbachol-induced contraction of PCLS. Treatment with TSA inhibited the 
      intracellular release of Ca(2+) in ASM cells in response to histamine, without 
      affecting the activation of Rho. The inhibition of HDAC abrogates airway 
      hyperresponsiveness to Mch in both naive and antigen-challenged mice. TSA 
      inhibits the agonist-induced contraction of PCLS and mobilization of Ca(2+) in 
      ASM cells. Thus, HDAC inhibitors demonstrate a mechanism of action distinct from 
      that of anti-inflammatory agents such as steroids, and represent a promising 
      therapeutic agent for airway disease.
FAU - Banerjee, Audreesh
AU  - Banerjee A
AD  - Translational Research Laboratories, Division of Pulmonary, Allergy, and Critical 
      Care Medicine, University of Pennsylvania Medical Center, 125 South 31st St., 
      Translational Research Laboratories, Philadelphia, PA 19104-3403, USA. 
      audreesh.banerjee@uphs.upenn.edu
FAU - Trivedi, Chinmay M
AU  - Trivedi CM
FAU - Damera, Gautam
AU  - Damera G
FAU - Jiang, Meiqi
AU  - Jiang M
FAU - Jester, William
AU  - Jester W
FAU - Hoshi, Toshinori
AU  - Hoshi T
FAU - Epstein, Jonathan A
AU  - Epstein JA
FAU - Panettieri, Reynold A Jr
AU  - Panettieri RA Jr
LA  - eng
GR  - K08 HL097032/HL/NHLBI NIH HHS/United States
GR  - K99 HL098366/HL/NHLBI NIH HHS/United States
GR  - R01GM057654/GM/NIGMS NIH HHS/United States
GR  - P30 ES013508/ES/NIEHS NIH HHS/United States
GR  - F32 HL096286/HL/NHLBI NIH HHS/United States
GR  - R01HL071546/HL/NHLBI NIH HHS/United States
GR  - R01 HL071546/HL/NHLBI NIH HHS/United States
GR  - K08HL097032/HL/NHLBI NIH HHS/United States
GR  - R01 HL097796/HL/NHLBI NIH HHS/United States
GR  - R01 GM078579/GM/NIGMS NIH HHS/United States
GR  - F32HL096286/HL/NHLBI NIH HHS/United States
GR  - K99-R00 HL098366/HL/NHLBI NIH HHS/United States
GR  - R01 GM057654/GM/NIGMS NIH HHS/United States
GR  - K99 HL098366-01/HL/NHLBI NIH HHS/United States
GR  - R01 HL081824/HL/NHLBI NIH HHS/United States
GR  - 5P30ES013-508-04/ES/NIEHS NIH HHS/United States
GR  - R00 HL098366/HL/NHLBI NIH HHS/United States
GR  - K99 HL098366-02/HL/NHLBI NIH HHS/United States
GR  - R00 HL098366-03/HL/NHLBI NIH HHS/United States
GR  - R01HL097796/HL/NHLBI NIH HHS/United States
GR  - R01GM078579/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Interleukin-6)
RN  - 207137-56-2 (Interleukin-4)
RN  - 3X2S926L3Z (trichostatin A)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - 8Y164V895Y (Carbachol)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Asthma/*physiopathology
MH  - Blotting, Western
MH  - Bronchoalveolar Lavage Fluid
MH  - Bronchoconstriction/*drug effects
MH  - Calcium/metabolism
MH  - Carbachol/pharmacology
MH  - Dexamethasone/pharmacology
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Female
MH  - Histone Deacetylase Inhibitors/*pharmacology
MH  - Humans
MH  - Hydroxamic Acids/*pharmacology
MH  - Inflammation/*prevention & control
MH  - Interleukin-4/metabolism
MH  - Interleukin-6/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Models, Biological
PMC - PMC3297166
EDAT- 2012/02/03 06:00
MHDA- 2012/03/27 06:00
PMCR- 2013/02/01
CRDT- 2012/02/03 06:00
PHST- 2012/02/03 06:00 [entrez]
PHST- 2012/02/03 06:00 [pubmed]
PHST- 2012/03/27 06:00 [medline]
PHST- 2013/02/01 00:00 [pmc-release]
AID - 46/2/132 [pii]
AID - 2010-0276OC [pii]
AID - 10.1165/rcmb.2010-0276OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2012 Feb;46(2):132-8. doi: 10.1165/rcmb.2010-0276OC.