Activation of poly(ADP-ribose) polymerase-1 is a central mechanism of lipopolysaccharide-induced acute lung inflammation

Lucas Liaudet, P. Á L Pacher, Jon G. Mabley, László Virág, Francisco G. Soriano, György Haskó, Csaba Szabo

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

Recent studies demonstrated that activation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) by oxidant-mediated DNA damage is an important pathway of tissue injury in conditions associated with oxidative stress. Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the phenanthridinone PARP inhibitor PJ-34, we now demonstrate an essential role of PARP-1 in the development of pulmonary inflammation induced by lipopolysaccharide (LPS). PARP-1+/+ and PARP-1-/- mice received an intratracheal instillation of LPS (50 μg), followed after 24 h by bronchoalveolar lavage to measure the cytokines TNF-α, IL-1β, and IL-6, the chemokines MIP-1α and MIP-2, leukocyte counts and myeloperoxidase activity (neutrophil accumulation), protein content (high permeability edema), and nitrite/nitrate (nitric oxide production). Malondialdehyde (an index of lipid peroxidation) was measured in lung tissue. Similar experiments were conducted in BALB/c mice treated with PJ-34 or vehicle. The absence of functional PARP-1 reduced LPS-induced increases of cytokines and chemokines, alveolar neutrophil accumulation, lung hyperpermeability, NO production, and lipid peroxidation. Histological analysis revealed attenuated lung damage after PARP inhibition. Our findings support a mechanistic role of PARP-1 in the regulation of LPS-induced lung inflammation. Pharmacological inhibition of PARP may be useful in clinical conditions associated with overwhelming lung inflammation.

Original languageEnglish (US)
Pages (from-to)372-377
Number of pages6
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume165
Issue number3
StatePublished - Feb 1 2002
Externally publishedYes

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Lipopolysaccharides
Pneumonia
Chemokines
Lung
Lipid Peroxidation
Neutrophils
Pharmacology
Cytokines
Genetic Suppression
Enzyme Activation
Bronchoalveolar Lavage
Nitrites
Malondialdehyde
Interleukin-1
Leukocyte Count
Oxidants
Nitrates
Peroxidase
DNA Damage
Poly (ADP-Ribose) Polymerase-1

Keywords

  • ARDS
  • Chemokines
  • Lipopolysaccharide
  • Lung
  • Poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Activation of poly(ADP-ribose) polymerase-1 is a central mechanism of lipopolysaccharide-induced acute lung inflammation. / Liaudet, Lucas; Pacher, P. Á L; Mabley, Jon G.; Virág, László; Soriano, Francisco G.; Haskó, György; Szabo, Csaba.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 165, No. 3, 01.02.2002, p. 372-377.

Research output: Contribution to journalArticle

Liaudet, Lucas ; Pacher, P. Á L ; Mabley, Jon G. ; Virág, László ; Soriano, Francisco G. ; Haskó, György ; Szabo, Csaba. / Activation of poly(ADP-ribose) polymerase-1 is a central mechanism of lipopolysaccharide-induced acute lung inflammation. In: American Journal of Respiratory and Critical Care Medicine. 2002 ; Vol. 165, No. 3. pp. 372-377.
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