In cystic fibrosis homozygotes and heterozygotes, neutrophil apoptosis is delayed and modulated by diamide or roscovitine: evidence for an innate neutrophil disturbance.
Cystic fibrosis (CF) is a chronic inflammatory lung disease characterized by polymorphonuclear neutrophil (PMN)-dominated airway inflammation. Defective apoptosis might explain PMN persistence at these inflammation sites. We previously reported that in CF patients PMN underwent delayed apoptosis, which was not always related to their infectious state and independent of the type of CF transmembrane regulator (CFTR) mutation. To understand the role of infection and PMN apoptosis in CF, PMN apoptosis was investigated in CF parents who are obligate heterozygotes for the CFTR mutation but without chronic bacterial infection. They also demonstrated delayed PMN apoptosis compared with healthy controls, as assessed by annexin-V labeling and caspase-3 cleavage. Diamide, a direct thiol-oxidizing agent, potentiated PMN apoptosis in controls and CF patients, resulting in similar levels of constitutive and Fas-potentiated apoptosis. The cyclin-dependent kinase inhibitor roscovitine provided another approach to restore normal PMN apoptosis. However, the selective CFTR inhibitor CFTR(Inh172) did not affect PMN apoptosis in control subjects. Apparently, the dysregulation of CF PMN is not only a consequence of the chronic infectious state in CF children but might also be related to CF 'intrinsic' factors. Restoration of normal PMN apoptosis by cellular redox modulation or roscovitine opens new research avenues to decrease PMN-mediated inflammation in CF.
Moriceau
Sandra
S
INSERM U845, Necker Hospital, Paris, France.
Lenoir
Gérard
G
Witko-Sarsat
Véronique
V
D000293:Adolescent; D017209:Apoptosis / Q000187:drug effects; D001424:Bacterial Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D001565:Benzoates / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002648:Child; D003550:Cystic Fibrosis / Q000150:complications / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D003958:Diamide / Q000494:pharmacology; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D053778:Thiazolidines / Q000494:pharmacology
C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001565:Benzoates; D011687:Purines; D053778:Thiazolidines; D000077546:Roscovitine; D003958:Diamide; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D053148:Caspase 3