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.
Department of Biomedical Sciences, Aging Research Center, CeSI, Gabriele D'Annunzio University Foundation, Via Colle dell'Ara, 66013 Chieti, Italy.
Domenico
D
Mattoscio
Virgilio
V
Evangelista
Raimondo
R
De Cristofaro
Antonio
A
Recchiuti
Assunta
A
Pandolfi
Sara
S
Di Silvestre
Stefano
S
Manarini
Nicola
N
Martelli
Bianca
B
Rocca
Giovanna
G
Petrucci
Daniela F
DF
Angelini
Luca
L
Battistini
Iole
I
Robuffo
Tiziana
T
Pensabene
Luisa
L
Pieroni
Maria Lucia
ML
Furnari
Francesca
F
Pardo
Serena
S
Quattrucci
Stefano
S
Lancellotti
Giovanni
G
Davì
Mario
M
Romano
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