title: Piceatannol modulates lung epithelial cellular responses to Pseudomonas aeruginosa.
abstract: Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen, which is the major cause of severe chronic lung infection in cystic fibrosis patients. It is also responsible for systemic infections in immunocompromised individuals and those presenting with significant pulmonary conditions in intensive care units. This microorganism has the capacity to initiate severe inflammation in infected lungs resulting in detrimental tissue damage. We have hypothesized that Syk protein tyrosine kinase mediates lung epithelial cellular responses to P. aeruginosa infection, and that a naturally occurring non-toxic Syk inhibitor piceatannol can protect infected human cells against the deleterious effects associated with this infection. We infected Syk-positive H292 or Syk-negative A549 human lung epithelial cell lines with P. aeruginosa and assessed the resulting cellular responses, i.e. production of proinflammatory cytokines, adhesion molecule expression, generation of reactive oxygen species, and apoptosis of infected cells, utilizing a multiplex bead-based immunoassay and flow cytometry. We also studied the internalization of P. aeruginosa using the gentamicin exclusion assay. We found that the piceatannol treatment significantly suppressed inflammation, oxidative stress and apoptosis in H292, but not in A549 cells implicating Syk participation in the regulation of the pathological processes induced by P. aeruginosa infection. Intriguingly, piceatannol was able to down-regulate the internalization of P. aeruginosa by both Syk-positive and Syk-negative cell lines, implying that the mechanisms of action of this compound extend beyond Syk inhibition. As piceatannol can interfere with several mechanisms of bacterial pathogenesis this natural compound deserves further study as a potential therapeutic option in P. aeruginosa infection.
authors.affiliation: Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University Campus, 955 Oliver Rd., Thunder Bay, ON, P7B 5E1, Canada. mulanova@nosm.ca.
authors.forename: Pouya Sadeghi
authors.initials: PS
authors.lastname: Aval
authors.forename: Jeff
authors.initials: J
authors.lastname: Werner
authors.forename: Ashley
authors.initials: A
authors.lastname: Cerqueira
authors.forename: Jazmyn
authors.initials: J
authors.lastname: Balfour-Boehm
authors.forename: Marina
authors.initials: M
authors.lastname: Ulanova
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D018384:Oxidative Stress / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology; D013267:Stilbenes / Q000494:pharmacology*; D000072377:Syk Kinase
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D013267:Stilbenes; D018799:Intercellular Adhesion Molecule-1; C041525:3,3',4,5'-tetrahydroxystilbene; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase