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1.  PLCB3 is a key modulator of IL-8 expression in cystic fibrosis bronchial epithelial cells 
Respiratory insufficiency is the major cause of morbidity and mortality in patients affected by cystic fibrosis. An excessive neutrophilic inflammation, mainly orchestrated by the release of IL-8 from bronchial epithelial cells and amplified by chronic bacterial infection with Pseudomonas aeruginosa, leads to progressive tissue destruction. The anti-inflammatory drugs presently utilized in cystic fibrosis patients have several limitations, indicating the need for identifying novel molecular targets. To address this issue, we preliminarily studied the association of 721 single-nucleotide polymorphisms from 135 genes potentially involved in signal transduction implicated in neutrophil recruitment in a cohort of F508del homozygous cystic fibrosis patients with either severe or mild progression of lung disease. The top ranking association was found for a nonsynonymous polymorphism of the phospholipase C beta 3 (PLCB3) gene. Studies in bronchial epithelial cells exposed to P.aeruginosa revealed that PLCB3 is implicated in extra cellular nucleotide–dependent intracellular calcium signaling, leading to activation of the protein kinase C alpha and beta and of the nuclear transcription factor NF-κB p65. The pro-inflammatory pathway regulated by PLCB3 acts by potentiating the Toll-like Receptors’ signaling cascade and represents an interesting molecular target to attenuate the excessive recruitment of neutrophils without completely abolishing the inflammatory response.
doi:10.4049/jimmunol.1003535
PMCID: PMC4166552  PMID: 21411730
2.  Pancreatic phenotype in infants with cystic fibrosis identified by mutation screening 
Archives of Disease in Childhood  2007;92(10):842-846.
Objective
To determine the pancreatic phenotype of infants with cystic fibrosis (CF) diagnosed in the first week of life by a combined immunoreactive trypsin/mutation screening program.
Design
A prospective evaluation of pancreatic function in infants with CF at the time of neonatal diagnosis and up to the age of 12.
Setting
Two different centres (Verona, Italy and Westmead, Australia) to enable comparison of results between two regions where <60% or ⩾90% of patients, respectively, have at least one single ΔF508 a mutation.
Patients
315 children with CF including 149 at Verona and 166 at Westmead.
Interventions
Fat balance studies over 3–5 days and pancreatic stimulation tests with main outcome measures being faecal fat or pancreatic colipase secretion. Patients with malabsorption are pancreatic insufficient (PI) or with normal absorption and pancreatic sufficient (PS).
Results
34 infants (23%) at Verona and 46 (28%) at Westmead were PS at diagnosis. 15% of those with two class I, II or III “severe” mutations and 26/28 (93%) of those with class IV or V mutations were PS at this early age. Of the 80 infants with PS, 20 became PI before the age of 12. All 20 had two severe mutations.
Conclusion
Neonatal mutational screening programs for CF are less likely to detect PS patients with non‐ΔF508 mutations. Of PS patients who are detected, those with two severe class I, II or III mutations are at particularly high risk of becoming PI during early childhood.
doi:10.1136/adc.2006.107581
PMCID: PMC2083233  PMID: 17449517
3.  Interaction of Adenovirus Type 5 Fiber with the Coxsackievirus and Adenovirus Receptor Activates Inflammatory Response in Human Respiratory Cells▿  
Journal of Virology  2006;80(22):11241-11254.
The innate immune response to adenovirus (Ad)-derived gene transfer vectors has been shown to initiate immediately after interaction of Ad with respiratory epithelial cells, through the induction of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and JNK mitogen-activated protein kinase (MAPK), nuclear factor κB (NF-κB), and different proinflammatory genes. Ad serotypes 2 or 5 (Ad2/5) enter respiratory epithelia after initial binding of fiber with the coxsackievirus-adenovirus receptor (CAR) or, alternatively, with cell surface heparan sulfate glycosaminoglycans. Ad2/5 internalization is triggered by binding of penton base to cellular RGD-binding integrins. Here we investigated the role of the Ad5 surface domain proteins constituting the vector capsid, namely, the fiber, the penton base, and the hexon, on the transmembrane signals leading to the transcription of the different proinflammatory genes in the human respiratory A549 cell line. Interaction of Ad fiber with CAR activates both ERK1/2 and JNK MAPK and the nuclear translocation of NF-κB, whereas no activation was observed after exposing A549 cells to penton base and hexon proteins. Moreover, interaction of Ad fiber with CAR, but not heparan sulfate proteoglycans, promotes transcription of the chemokines interleukin-8, GRO-α, GRO-γ, RANTES, and interferon-inducible protein 10. These results identify the binding of Ad5 fiber with the cellular CAR as a key proinflammatory activation event in epithelial respiratory cells that is independent of the transcription of Ad5 genes.
doi:10.1128/JVI.00721-06
PMCID: PMC1642173  PMID: 16956941

Results 1-3 (3)