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Therapeutic potential of a new phosphodiesterase inhibitor in acute lung injury

¹ Laboratory of Respiration Physiology, Carlos Chagas Filho Biophysics Institute, ² Dept of Medical Biochemistry and ³ Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

CORRESPONDENCE: W.A. Zin, Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho - C.C.S., Laboratório de Fisiologia da Respiração Ilha do Fundão, 21949-900 - Rio de Janeiro, Brazil. Fax: 55 2122808193. E-mail: wazin@biof.ufrj.br

Keywords: inflammation, lung morphometry, phosphodiesterase inhibitor, respiratory mechanics

Received: November 26, 2002
Accepted March 16, 2003

This study was supported by the Centres of Excellence Programme (PRONEX-MCT), Brazilian Council for Scientific and Technological Development (CNPq), Financing for Studies and Projects (FINEP) and Rio de Janeiro State Research Supporting Foundation (FAPERJ).

The effects of LASSBio596, a phosphodiesterase type-4 and -5 inhibitor, were tested in Escherichia coli lipopolysaccharide (LPS)-induced acute lung injury.

Twenty-four BALB/c mice were randomly divided into four groups. In the control group, saline (0.05 mL) was injected intratracheally (i.t.). The LPS group received LPS (10 µg i.t., 0.05 mL). In the LASSBio596 groups, LASSBio596 (10 mg·kg^–1, 0.2 mL) was injected intraperitoneally 1 h before or 6 h after LPS administration. After 24 h, in vivo (lung resistive and viscoelastic pressures, and static and dynamic elastances) and in vitro (tissue resistance, elastance and hysteresivity) pulmonary mechanics, lung morphometry and collagenous fibre content were computed. Neutrophils and tumour necrosis factor (TNF)- levels were evaluated in the bronchoalveolar lavage fluid.

LASSBio596 prevented the changes in lung mechanics, and inhibited neutrophilic recruitment, TNF- release, bronchoconstriction, alveolar collapse and the increment of collagen fibre content induced by LPS, independently of the moment of injection.

In conclusion, LASSBio596 modulated the lung inflammatory process and had the potential to block fibroproliferation. Thus, agents that inhibit phosphodiesterase 4 and 5 simultaneously may be a useful adjunct therapy for acute lung injury.

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