Effects of theophylline on chronic inflammatory lung injury induced by LPS exposure in guinea pigs.
BACKGROUND
Pathogenesis of COPD is, at least in part, attributable to the chronic accumulation of neutrophils in the airways, and morphological changes such as hyperplasia of goblet cells in the airways are often observed in this disease. These structural changes were induced in guinea pigs by repetitive inhalations of LPS, and the effects of theophylline and dexamethasone were examined.


METHODS
Male Hartley Guinea pigs weighing about 300 g were exposed to a nebulized solution of LPS (30 microg/mL) for 1 hour. Exposure to LPS was performed 15 times at 48-hour intervals. Histological analysis was performed, and infiltration of leukocytes in BALF, airway hyperreactivity and hydroxyproline content of the lung were measured 24 or 48 hours after the final exposure of LPS. Drugs were administered every day until 30 minutes before the final exposure.


RESULTS
Repetitive exposure to LPS induced an influx of inflammatory cells into the BALF. Histological changes such as accumulation of inflammatory cells in the lung parenchyma, enlargement of alveoli, swelling of the alveolar walls and goblet cell hyperplasia in the airways were observed. Airway hyperreactivity and increased lung hydroxyproline content were also found in this model of chronic inflammatory lung injury. Some of these changes induced by repetitive LPS exposure were improved by treatment with theophylline or dexamethasone.


CONCLUSIONS
Theophylline improved airway injury as well as airway hyperreactivity induced by repetitive exposure of the guinea pigs to LPS. These results suggest that theophylline treatment has ameliorative effects on airway disease with chronic inflammation.
Kaneko
Yoshio
Y
Department of Pharmacology, Pharmaceutical Research Laboratories, Kowa Pharmaceutical Co. Ltd., Higashimurayama-shi, Tokyo, Japan. y-kaneko@kowa-souyaku.co.jp
Takashima
Kazumi
K
Suzuki
Naomi
N
Yamana
Kenjiro
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002908:Chronic Disease; D006168:Guinea Pigs; D006909:Hydroxyproline / Q000378:metabolism; D018836:Inflammation Mediators / Q000627:therapeutic use / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008171:Lung Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013806:Theophylline / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D013806:Theophylline; D006909:Hydroxyproline