title: Cyclin-dependent kinase inhibition reduces lung damage in a mouse model of ventilator-induced lung injury.
abstract: Mechanical ventilation (MV) has the potential to induce lung damage in healthy lungs or aggravate existing lung injury. Polymorphonuclear neutrophil (PMN) recruitment plays an important role in driving the inflammatory response in ventilator-induced lung injury (VILI). The cyclin-dependent kinase inhibitor r-roscovitine has been shown to induce apoptosis in PMNs. In this study, we investigated the potential of r-roscovitine treatment in reducing lung damage in a mouse model of VILI. Mice were tracheotomized and subjected to lung-protective MV with lower (∼7.5 mL/kg) or lung-injurious MV with higher (∼15 mL/kg) tidal volume (VT). R-roscovitine treatment enhanced apoptosis in PMNs in vitro. Ventilator-induced lung injury was associated with pulmonary PMN influx in low and high VT MV. During lung-injurious MV, r-roscovitine treatment reduced the number of PMNs and lowered levels of the lung damage markers RAGE (receptor for advanced glycation end products) and total immunoglobulin M in bronchoalveolar lavage fluid. R-roscovitine did not affect cytokine or chemokine levels in the bronchoalveolar space, neither during lung-protective nor lung-injurious MV. Thus, r-roscovitine treatment reduces lung damage in VILI, possibly dependent on increased apoptosis of PMNs.
authors: Center for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands. a.j.hoogendijk@amc.uva.nl
authors: Arie J
authors: AJ
authors: Hoogendijk
authors: Maria T
authors: MT
authors: Kuipers
authors: Tom
authors: T
authors: van der Poll
authors: Marcus J
authors: MJ
authors: Schultz
authors: Catharina W
authors: CW
authors: Wieland
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D000077546:Roscovitine; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012122:Ventilators, Mechanical / Q000009:adverse effects
chemical_list: D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011687:Purines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases