The effects of post-treatment with lisofylline, a phosphatidic acid generation inhibitor, on sepsis-induced acute lung injury in pigs

Naoki Hasegawa, Yoshio Oka, Mitsuo Nakayama, Gerald J. Berry, Stuart Bursten, Glenn Rice, Thomas A. Raffin

Research output: Contribution to journalArticle

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Abstract

The effects of lisofylline [(R)-1-(5-hydroxyhexyl)-3,7- dimethylxanthine] (LSF), an inhibitor of de novo phosphatidic acid (PA) generation, on sepsis-induced acute lung injury was studied using Hanford minipigs weighing 18 to 25 kg. Sepsis was induced by an intravenous infusion of Pseudomonas aeruginosa (1 x 106/colony-forming units/kg/min over 2 h). Saline was used as the control vehicle. Six groups were studied: saline control group (SALINE: n = 5); sepsis control group (SEPSIS: n = 5); LSF control group (LSF: n = 5), which received a 25-mg/kg bolus of LSF 30 min before time zero followed by continuous infusion of 10 mg/kg/h throughout the study; LSF-treated septic groups, which were treated with LSF 30 min prior to sepsis (Pre: n = 5), 1 h postonset (Post-1 h: n = 8) or 2 h postonset (Post- 2 h: n = 8) of the bacterial infusion, Hemodynamics, PA(O2), neutrophil counts, and plasma porcine tumor necrosis factor-α concentrations were monitored for 6 h. After the minipigs were killed, lung tissue was sampled to measure wet-to-dry weight ratio (W/D), tissue albumin index (TAI), thiobarbituric acid-reactive material content (TBARM), and myeloperoxidase (MPO) activity. Compared with the SALINE group, the SEPSIS group showed significant systemic hypotension, pulmonary hypertension, arterial hypoxemia, neutropenia, and increase in TNF-α, MPO activity, W/D, TBARM, and TAI. LSF treatment attenuated sepsis-induced pulmonary hypertension, neutropenia, and hypoxemia, and increased MPO activity and lung injury measurements in the Pre and Post-1 h groups, but its efficacy was blunted in the Post-2 h group. Plasma TNF-α was decreased only in the Pre group. Thus, inhibition of intracellular PA generation through de novo pathways attenuates sepsis- induced acute lung injury.

Original languageEnglish
Pages (from-to)928-936
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume155
Issue number3
Publication statusPublished - 1997
Externally publishedYes

Fingerprint

lisofylline
Phosphatidic Acids
Acute Lung Injury
Sepsis
Swine
Peroxidase
Miniature Swine
Neutropenia
Pulmonary Hypertension
Control Groups
Albumins
Therapeutics
Lung Injury
Intravenous Infusions
Hypotension
Pseudomonas aeruginosa
Neutrophils
Stem Cells
Tumor Necrosis Factor-alpha
Hemodynamics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

The effects of post-treatment with lisofylline, a phosphatidic acid generation inhibitor, on sepsis-induced acute lung injury in pigs. / Hasegawa, Naoki; Oka, Yoshio; Nakayama, Mitsuo; Berry, Gerald J.; Bursten, Stuart; Rice, Glenn; Raffin, Thomas A.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 155, No. 3, 1997, p. 928-936.

Research output: Contribution to journalArticle

Hasegawa, Naoki ; Oka, Yoshio ; Nakayama, Mitsuo ; Berry, Gerald J. ; Bursten, Stuart ; Rice, Glenn ; Raffin, Thomas A. / The effects of post-treatment with lisofylline, a phosphatidic acid generation inhibitor, on sepsis-induced acute lung injury in pigs. In: American Journal of Respiratory and Critical Care Medicine. 1997 ; Vol. 155, No. 3. pp. 928-936.
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