Activation of Poly(ADP-Ribose) Polymerase-1 Is a Central Mechanism of Lipopolysaccharide-Induced Acute Lung Inflammation

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 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.

Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: evidence for the role of adenosine A2 receptors

“…Our results are in agreement with literature that describes adenosine and inosine as critical molecules involved in the regulation of inflammatory and immune processes [20,[30][31][32]. Adenosine accumulates in the extracellular space in response to metabolic stress and cell damage, and elevations in extracellular adenosine are found in conditions of ischemia, hypoxia, inflammation, and trauma [33,34].…”

“…Inosine also is known to exert wide raging anti-inflammatory effects that include inhibition of pro-inflammatory cytokine, chemokine production, protection in septic shock, colitis, and acute lung injury [31,45,46]. Some studies have shown that inosine can stimulate adenosine A 2A receptors and is protective in models of Concanavalin A-induced liver damage, endotoxininduced sepsis [20,47], and TNBS-induced colitis [21].…”

Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs

“…In the lungs, PARP plays a key role in the microvascular platelet-endothelial cell interaction induced by endotoxin, acute lung inflammation following intratracheal administration of endotoxin, induction of asthma, an leukocyte recruitment in systemic endotoxemia [6,42,43]. These cellular interactions, tissue inflammatory changes and subsequent alterations in adhesion molecules are likely to be the fundamental basis for the pathogenesis of lung injury.…”

NAD+-Consuming Enzymes in the Regulation of Lung Immune Responses

“…1C). Alveolar neutrophil accumulation, hyperreactivity and lung damage were also attenuated [69]. PARP-1 gene silencing or inhibition by niacinamide, but not by PJ-34, also diminished IL-1 and MIP-2 expression [69,70].…”

“…In 2002, Liaudet et al [69] demonstrated that the absence of functional PARP-1 reduced LPS-induced cytokine expression (TNF-, MIP-1 and IL-6), NO production, and lipid peroxidation (Fig. 1C).…”