title: Mesenteritis precedes vasculitis in the rat mesentery after subacute administration of a phosphodiesterase type 4 inhibitor.
abstract: Inhibitors of phosphodiesterase type 4 (PDE4) are currently exploited as potent drugs for pulmonary diseases. Some PDE4 inhibitors induce necrotizing panarteritis in the mesentery of rats, comparable to spontaneous polyarteritis nodosa in rats and vascular alterations that are induced by various vasoactive compounds, such as fenoldopam and inhibitors of PDE3. The mechanism of toxicity is unknown. In order to investigate the development of arteritis in the splanchnic vasculature of rats, a time-course study was performed with high doses of a compound (BYK169171), specifically inhibiting PDE4. Rats were treated orally for 1-28 days, and alterations in the mesentery were evaluated by histology, morphometry, and immunohistology. As early as 3 days after the onset of treatment, a mesenteritis was found, characterized by macrophage infiltration, fibroblast proliferation, neovascularization, and loss of adipocytes. Incidence and severity of the mesenteritis were low during the first 2 weeks of treatment, but increased with duration of treatment, finally affecting 2/3 of all animals. A segmental necrotizing panarteritis was detected in some rats treated for 21 or 28 days, but always followed a mesenteritis, whereas many animals with mesenteric inflammation did not have vascular lesions. We postulate that PDE4 inhibitors do not cause a primary vasculitis/arteritis in rats, but induce a non-purulent inflammation as the predominant initial toxic effect in the mesentery. This renders their toxic effect distinct from that of PDE3 inhibitors.
authors.affiliation: Altana Pharma AG, Department of Pathology and Toxicology, 22047 Hamburg, Germany. lars.mecklenburg@altanapharma.com
authors.forename: Lars
authors.initials: L
authors.lastname: Mecklenburg
authors.forename: Anke
authors.initials: A
authors.lastname: Heuser
authors.forename: Tobias
authors.initials: T
authors.lastname: Juengling
authors.forename: Manfred
authors.initials: M
authors.lastname: Kohler
authors.forename: Roman
authors.initials: R
authors.lastname: Foell
authors.forename: Deborah
authors.initials: D
authors.lastname: Ockert
authors.forename: Klaus
authors.initials: K
authors.lastname: Tuch
authors.forename: Gerd
authors.initials: G
authors.lastname: Bode
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D007583:Jejunum / Q000187:drug effects / Q000473:pathology; D008297:Male; D008643:Mesentery / Q000187:drug effects* / Q000473:pathology; D010538:Peritonitis / Q000139:chemically induced* / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D014657:Vasculitis / Q000139:chemically induced / Q000473:pathology
chemical_list: D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4