Cystic fibrosis transmembrane conductance regulator (CFTR) expression in human platelets: impact on mediators and mechanisms of the inflammatory response.
Inflammatory lung disease is a primary cause of morbidity and mortality in cystic fibrosis (CF). Mechanisms of unresolved acute inflammation in CF are not completely known, although the involvement of cystic fibrosis transmembrane conductance regulator (CFTR) in nonrespiratory cells is emerging. Here we examined CFTR expression and function in human platelets (PLTs) and found that they express a biologically active CFTR. CFTR blockade gave an ∼50% reduction in lipoxin A(4) (LXA(4)) formation during PLT/polymorphonuclear leukocytes (PMN) coincubations by inhibiting the lipoxin synthase activity of PLT 12-lipoxygenase. PLTs from CF patients generated ∼40% less LXA(4) compared to healthy subject PLTs. CFTR inhibition increased PLT-dependent PMN viability (33.0±5.7 vs. 61.2±8.2%; P=0.033), suppressed nitric oxide generation (0.23±0.04 vs. 0.11±0.002 pmol/10(8) PLTs; P=0.004), while reducing AKT (1.02±0.12 vs. 0.71±0.007 U; P=0.04), and increasing p38 MAPK phosphorylation (0.650±0.09 vs. 1.04±0.24 U; P=0.03). Taken together, these findings indicate that PLTs from CF patients are affected by the molecular defect of CFTR. Moreover, this CF PLT abnormality may explain the failure of resolution in CF.
Mattoscio
Domenico
D
Department of Biomedical Sciences, Aging Research Center, CeSI, Gabriele D'Annunzio University Foundation, Via Colle dell'Ara, 66013 Chieti, Italy.
Evangelista
Virgilio
V
De Cristofaro
Raimondo
R
Recchiuti
Antonio
A
Pandolfi
Assunta
A
Di Silvestre
Sara
S
Manarini
Stefano
S
Martelli
Nicola
N
Rocca
Bianca
B
Petrucci
Giovanna
G
Angelini
Daniela F
DF
Battistini
Luca
L
Robuffo
Iole
I
Pensabene
Tiziana
T
Pieroni
Luisa
L
Furnari
Maria Lucia
ML
Pardo
Francesca
F
Quattrucci
Serena
S
Lancellotti
Stefano
S
Davì
Giovanni
G
Romano
Mario
M
D017209:Apoptosis; D001792:Blood Platelets / Q000378:metabolism*; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000097:blood*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018836:Inflammation Mediators; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D011494:Protein Kinases