Activation of poly(ADP-Ribose) polymerase-1 is a central mechanism of lipopolysaccharide-induced acute lung inflammation.
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 microg), followed after 24 h by bronchoalveolar lavage to measure the cytokines TNF-alpha, IL-1beta, and IL-6, the chemokines MIP-1alpha 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.
Liaudet
Lucas
L
Inotek Corporation, Suite 419 E, 100 Cummings Drive, Beverly, MA 01915, USA.
Pacher
Pál
P
Mabley
Jon G
JG
Virág
László
L
Soriano
Francisco G
FG
Haskó
György
G
Szabó
Csaba
C
D000818:Animals; D004926:Escherichia coli; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000209:etiology*
D008070:Lipopolysaccharides; D011065:Poly(ADP-ribose) Polymerases