Effects of intratracheal tumor necrosis factor-alpha plasmid vector on lipopolysaccharide lethality and lung injury in mice

Marcienne M. Wright, Charles S. Powell, Robert M. Jackson

Research output: Contribution to journalArticlepeer-review

Abstract

Bacterial lipopolysaccharide (LPS) causes acute lung injury (ALJ) and contributes to inflammation in the acute respiratory distress syndrome (ARDS) and sepsis, making mechanisms of resistance to LPS critically important in clinical settings. The authors postulated that intratracheal administration of a plasmid (pcDNA3.0-rTNFα) encoding rat tumor necrosis factor-alpha (TNF-α) would increase resistance of mice to LPS-induced ALI or mortality. They investigated the time course and dose-response for development of LPS-induced ALI in C57/BL6 mice and sought possible protective effects of 100 μg pcDNA3.0-rTNFα intratracheally 1, 2, or 3 weeks before LPS challenge. Lung myeloperoxidase (MPO) activity and alveolar lavage fluid (BALF) cell counts increased significantly 48 hours after intraperitoneal (IP) LPS challenges. After pcDNA3.0-rTNFα pretreatment, mice challenged with LPS had lower lung/body weight ratios than mice treated with pcDNA3.0; however, other indices of lung injury did not differ. Survival of mice challenged with lethal IP LPS 2 weeks after intratracheal pcDNA3.0-rTNFα vector improved significantly, compared to mice pretreated with the control vector, pcDNA3.0. However, pcDNA3.0-pretreated mice tolerated LPS challenge less well than saline-pretreated controls. LPS causes neutrophilic lung injury and mortality, but pcDNA3.0-TNFα does not prevent ALI due to LPS. Intratracheal pcDNA3.0-rTNFα pretreatment significantly improves survival of mice after LPS challenge, compared to those pretreated with pcDNA3.0.

Original languageEnglish (US)
Pages (from-to)653-671
Number of pages19
JournalExperimental Lung Research
Volume30
Issue number8
DOIs
StatePublished - Dec 1 2004

Keywords

  • ARDS
  • DNA vaccination
  • Endotoxin
  • Lipopolysaccharide

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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