rhinosinusitis, cough reflex

[Guest guest]

Vascular endothelial growth factor drives autocrine epithelial cell

proliferation and survival in chronic rhinosinusitis with nasal polyposis.

Lee Hyun Sil; Myers ; Kim (Profiled Author: MYERS, ALLEN)

s Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Room

3B65A, Baltimore, MD 21224, USA.

American journal of respiratory and critical care medicine 2009;180(11):1056-67.

PubMedAbstract

RATIONALE: The pathogenesis of nasal polyps in chronic rhinosinusitis is poorly

understood. OBJECTIVES: These studies seek to implicate a functional role for

vascular endothelial growth factor (VEGF) in perpetuating primary nasal

epithelial cell overgrowth, a key feature of hyperplastic polyps. METHODS:

Comparison of VEGF and receptor expression was assessed by ELISA of nasal

lavage, immunohistochemistry of sinus tissue, flow cytometry of nasal epithelial

cells, and ELISA of supernatants. VEGF-dependent cell growth and apoptosis were

assessed with blocking antibodies to VEGF, their receptors, or small interfering

RNA knockdown of neuropilin-1 by cell proliferation assays and flow cytometric

binding of annexin V. MEASUREMENTS AND MAIN RESULTS: VEGF protein was sevenfold

higher in nasal lavage from patients with polyposis compared with control

subjects (P < 0.001). We also report elevated expression of VEGF (P < 0.012),

receptors VEGFR2 and phospho-VEGFR2 (both P < 0.04), and identification of VEGF

coreceptor neuropilin-1 in these tissues. Nasal epithelial cells from patients

with polyps demonstrated faster growth rates (P < 0.005). Exposure of cells to

blocking antibodies against VEGF resulted in inhibition of cell growth (P <

0.05). VEGF receptor blockade required blockade of neuropilin-1 (P < 0.05) and

resulted in increased apoptosis (P < 0.001) and inhibition of autocrine

epithelial VEGF production (P < 0.05). CONCLUSIONS: These data demonstrate that

VEGF is a novel biomarker for chronic rhinosinusitis with hyperplastic sinonasal

polyposis that functions in an autocrine feed-forward manner to promote nasal

epithelial cell growth and to inhibit apoptosis. These findings implicate a

previously unrecognized and novel role of VEGF functioning through neuropilin-1

on nonneoplastic primary human airway epithelial cells, to amplify cell growth,

contributing to exuberant hyperplastic polyposis.

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Selective expression of a sodium pump isozyme by cough receptors and evidence

for its essential role in regulating cough.

Mazzone Stuart B; Reynolds M; Mori Nanako; Kollarik n; Farmer

G; Myers C; Canning n J (Profiled Authors: KOLLARIK, MARIAN; MYERS,

ALLEN; CANNING, BRENDAN)

School of Biomedical Sciences, The University of Queensland, St Lucia,

Queensland, Australia.

The Journal of neuroscience : the official journal of the Society for

Neuroscience 2009;29(43):13662-71.

PubMedAbstract

We have identified a distinct subtype of airway vagal afferent nerve that plays

an essential role in regulating the cough reflex. These afferents are

exquisitely sensitive to punctate mechanical stimuli, acid, and decreases in

extracellular chloride concentrations, but are insensitive to capsaicin,

bradykinin, histamine, adenosine, serotonin, or changes in airway intraluminal

pressures. In this study we used intravital imaging, retrograde neuronal

tracing, and electrophysiological analyses to characterize the structural basis

for their peculiar mechanical sensitivity and to further characterize the

regulation of their excitability. In completing these experiments, we uncovered

evidence for an essential role of an isozyme of Na(+)-K(+) ATPase in regulating

cough. These vagal sensory neurons arise bilaterally from the nodose ganglia and

are selectively and brilliantly stained intravitally with the styryl dye FM2-10.

Cough receptor terminations are confined and adherent to the extracellular

matrix separating the airway epithelium and smooth muscle layers, a site of

extensive remodeling in asthma and chronic obstructive pulmonary disease. The

cough receptor terminals uniquely express the alpha(3) subunit of Na(+)-K(+)

ATPase. Intravital staining of cough receptors by FM2-10, cough receptor

excitability in vitro, and coughing in vivo are potently and selectively

inhibited by the sodium pump inhibitor ouabain. These data provide the first

detailed morphological description of the peripheral terminals of the sensory

nerves regulating cough and identify a selective molecular target for their

modulation.