Role of poly(ADP-ribose) synthetase in pulmonary leukocyte recruitment

Abstract

During systemic inflammation, recruitment and activation of leukocytes in the pulmonary microcirculation may result in a potentially life-threatening acute lung injury. We elucidated the role of the poly(ADP-ribose) synthetase (PARS), a nucleotide-polymerizing enzyme, in the regulation of leukocyte recruitment within the lung with regard to the localization in the pulmonary microcirculation and in correlation to hemodynamics in the respective vascular segments and expression of intercellular adhesion molecule 1 during endotoxemia. Inhibition of PARS by 3-aminobenzamide reduced the endotoxin-induced leukocyte recruitment within pulmonary arterioles, capillaries, and venules in rabbits as quantified by in vivo fluorescence microscopy. Microhemodynamics and thus shear rates in all pulmonary microvascular segments remained constant. Simultaneously, inhibition of PARS with 3-aminobenzamide suppressed the endotoxin-induced adhesion molecules expression as demonstrated for intercellular adhesion molecule 1 by immunohistochemistry and Western blot analysis. We confirmed this result with the use of PARS knockout mice. The inhibitory effect of 3-aminobenzamide on leukocyte recruitment was associated with a reduction of pulmonary capillary leakage and edema formation. We first provide evidence that PARS activation mediates the leukocyte sequestration in pulmonary microvessels through upregulation of adhesion molecules. As reactive oxygen species released from leukocyte are supposed to cause an upregulation of adhesion molecules we conclude that PARS inhibition contributes to termination of this vicious cycle and inhibits the inflammatory process.

Nicotinamide abrogates acute lung injury caused by ischaemia/reperfusion

“…Pharmacological inhibition and gene knockout mutants of PARS or PARP have become a new approach for the experimental therapy of various disorders, such as endotoxin shock, stroke, I/R injury, lung inflammation and others [6,7,17,[20][21][22][23]. Activation of PARS or PARP produces cytotoxicity and subsequent cell death and organ dysfunction [24].…”

“…In the lungs, PARS or PARP play a key role in the microvascular platelet-endothelial cell interaction induced by: endotoxin; acute lung inflammation following intratracheal administration of endotoxin; induction of asthma; and leukocyte recruitment in systemic endotoxaemia [8,[21][22][23]. These cellular interactions, tissue inflammatory changes and associated changes in adhesion molecules are likely to be the fundamental basis for the pathogenesis of lung injury.…”

Poly(ADP-ribose) polymerase 1 at the crossroad of metabolic stress and inflammation in aging

“…In animal studies, PARP inhibition and/or PARP1 deficiency is effective in different age-related diseases [119]. The PARP inhibitor 5-AIQ has been demonstrated to attenuate the expression of P-selectin and intracellular adhesion molecule-1 (ICAM-1) as well as the recruitment of neutrophils and leukocytes into the injured lung [124,125]. Thus, application of inhibitors reduces the degree of acute inflammation and tissue damage associated with experimental lung injury.…”

Red blood cells induce hypoxic lung inflammation

“…A small portion of isolated RBCs were labeled with fluorescein isothiocyanate (FITC) as previously described. 17 The native and FITC-labeled RBCs were resuspended in HEPES and reinfused. In several experiments we modified the isolated RBCs by the following procedures before microinfusing them into experimental microvessels: (1) CO. To replace O 2 bound to Hb with CO, the RBCs were flushed with 100% CO for 5 minutes.…”