Inhibition of acute pulmonary and systemic inflammation by 1,7-dimethylxanthine.
The nuclear enzyme poly(ADP-ribose) polymerse-1 (PARP-1) has previously been reported to play an important role in lipopolysaccharide (LPS)-induced pulmonary inflammation and is highly activated in COPD patients. In the present study, the anti-inflammatory efficacy of a previously identified poly(ADP-ribose) polymerase-1 (PARP-1) inhibiting caffeine metabolite, 1,7-dimethylxanthine, was both in vivo as well as ex vivo evaluated. Orally administered 1,7-dimethylxanthine significantly attenuated lung myeloperoxidase-levels, transcription of IL-6, TNF-alpha, MIP1alpha and MIP2 genes as well as PAR-polymer formation in a mouse model of intratracheally LPS-induced acute pulmonary inflammation. Serum amyloid P component and plasma IL-6 were also lowered in 1,7-dimethylxanthine treated mice, indicating a reduced systemic inflammatory response. In addition, at 24h after LPS administration anti-inflammatory effects of 1,7-dimethylxanthine appeared more pronounced than those of the orally administered PARP-1 inhibitor 3-aminobenzamide. In the second model, in blood of COPD-patients and healthy controls ex vivo pre-incubated with a physiological concentration of 1,7-dimethylxanthine (10microM), LPS-induced production of the cytokines IL-6 and TNF-alpha was significantly suppressed. 1,7-Dimethylxanthine exerts anti-inflammatory effects, both in vivo mouse as well as ex vivo human. These results suggest that the PARP-1 inhibiting caffeine metabolite 1,7-dimethylxanthine may have therapeutic potential in pulmonary inflammatory diseases such as COPD.
Geraets
Liesbeth
L
Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, PO Box 616,6200 MD Maastricht, The Netherlands. liesbeth.geraets@rivm.nl
Haegens
Astrid
A
Weseler
Antje R
AR
Brauers
Karen
K
Vernooy
Juanita H J
JH
Wouters
Emiel F M
EF
Bast
Aalt
A
Hageman
Geja J
GJ
D000284:Administration, Oral; D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D013806:Theophylline / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D001549:Benzamides; D016207:Cytokines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011064:Poly Adenosine Diphosphate Ribose; C025160:3-aminobenzamide; D013806:Theophylline; D009195:Peroxidase; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C021183:1,7-dimethylxanthine