Conserved responses to trichostatin A in rodent lungs exposed to endotoxin or stretch.
Histone deacetylase (HDAC) isoenzymes have been suggested as possible drug targets in pulmonary cancer and in inflammatory lung diseases such as asthma and COPD. Whether HDAC inhibition is pro- or anti-inflammatory is under debate. To further examine this clinically relevant paradigm, we analyzed 8 genes that are upregulated by two pro-inflammatory stimuli, i.e. endotoxin and mechanical stress (overventilation), in isolated rat and mouse lungs, respectively. We studied the effect of the HDAC inhibitor trichostatin A (TSA) under control conditions, in response to endotoxin and overventilation, and on the effects of the steroid dexamethasone. TSA affected gene expression largely independent of the stimulus (endotoxin, overventilation) and the species (rat, mouse) leading to upregulation of some genes (Tnf, Cxcl2) and downregulation of others (Cxcl10, Timp1, Selp, Il6). At the protein level, TSA reduced the stimulated release of TNF, MIP-2alpha and IL-6, indicating that TSA may affect protein translation independent from gene transcription. In general, the anti-inflammatory effects of TSA on gene expression and protein release were additive to that of dexamethasone, suggesting that both drugs employ different mechanisms. We conclude that pro-inflammatory stimuli induce distinct sets of genes that are regulated by HDAC in a diverse, but consistent manner across two rodent species. The present findings together with previous in vivo studies suggest that the effect of HDAC inhibition in the intact lung is in part anti-inflammatory.
Dombrowsky
Heike
H
Division of Pulmonary Pharmacology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
Barrenschee
Martina
M
Kunze
Maren
M
Uhlig
Stefan
S
D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D004731:Endotoxins; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008170:Lung Compliance / Q000187:drug effects; D008171:Lung Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D012121:Respiration, Artificial; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013213:Starch; D013990:Tidal Volume / Q000502:physiology
D016207:Cytokines; D017931:DNA Primers; D004731:Endotoxins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D013213:Starch