Background and purpose: Airway remodelling in asthma is manifested, in part, as increased airway smooth muscle (ASM) mass, reflecting myocyte proliferation. We hypothesized that calcitriol, a secosteroidal vitamin D receptor (VDR) modulator, would inhibit growth factor‐induced myocyte proliferation.Experimental approach: Human ASM cell cultures were derived from bronchial samples taken during surgery. ASM cells were treated with platelet‐derived growth factor (PDGF) (10 ng·mL−1) for 24 h in the presence of calcitriol, dexamethasone or a checkpoint kinase 1 (Chk1) inhibitor (SB218078). The effects of calcitriol on PDGF‐mediated cell proliferation were assessed by thymidine incorporation assay, propidium iodide‐based cell cycle analysis, caspase‐3 assay and immunoblotting for specific cell cycle modulators.Key results: Calcitriol, but not dexamethasone, inhibited PDGF‐induced ASM DNA synthesis concentration dependently (IC50= 520 ± 52 nM). These effects were associated with VDR‐mediated expression of cytochrome CYP24A1 with no effects on ASM apoptosis. Calcitriol substantially inhibited (P < 0.01) PDGF‐stimulated cell growth in ASM derived from both normal (59 ± 8%) and asthmatic subjects (57 ± 9%). Calcitriol inhibited PDGF‐induced phosphorylation of retinoblastoma protein (Rb) and Chk1, with no effects on PDGF‐mediated activation of extracellular signal‐regulated kinases 1/2, PI3‐kinase and S6 kinase, or expression of p21Waf/Cip‐1, p27Kip1, cyclin D and E2F‐1. Consistent with these observations, SB218078 also inhibited (IC50= 450 ± 100 pM) PDGF‐induced cell cycle progression.Conclusions and implications: Calcitriol decreased PDGF‐induced ASM cell growth by inhibiting Rb and Chk1 phosphorylation.This Research Paper is the subject of a Commentary in this issue by Clifford and Knox (pp. 1426–1428). To view this article visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009

Background and purpose: Chemokines play a critical role in the pathogenesis of asthma and facilitate the recruitment of inflammatory cells in the airways. Evidence now suggests that airway smooth muscle (ASM) may serve as a source of chemokines in inflamed airways. Although vitamin D has potent anti-inflammatory properties in vitro in some cell types, its effects on ASM cells remain unclear. Here, we investigated whether 1 alpha, 25-dihydroxy vitamin D-3 (calcitriol) modulated chemokine production in ASM.Experimental approach: Human ASM cell cultures were derived from tracheal samples taken during surgery. ASM cells were treated with tumour necrosis factor alpha (TNF alpha) and/or interferon gamma (IFN gamma) for 24 h in the presence of calcitriol and/or the glucocorticoid fluticasone added 2 h before. RANTES (regulated upon activation, normal T-cell expressed and secreted), interferon-inducible protein 10 (IP-10) and fractalkine (FKN) levels in cell supernatants were measured by ELISA.Key results: In TNF alpha-treated cells, calcitriol inhibited RANTES and IP-10 secretion in a concentration-dependent manner. FKN levels were negligible. In TNF alpha/IFN gamma-treated cells, whereas fluticasone or calcitriol alone partially inhibited RANTES secretion (by 38 and 20%, respectively), the combination of both drugs additively inhibited RANTES secretion (by 60%). No effect was observed on IP-10 secretion. Whereas fluticasone enhanced FKN secretion (by 50%), calcitriol significantly decreased FKN levels (by 50%). Interestingly, calcitriol blocked the stimulatory effect of fluticasone on FKN secretion, which was inhibited by 60% with the combination of calcitriol and fluticasone.Conclusions and implications: These findings suggest that vitamin D uniquely modulates human ASM expression of chemokines and may exert some beneficial effects in the treatment of steroid-resistant patients with asthma.

The diiractive production of 0 (770) mesons in muon-proton interactions is studied in the kinematic region 0.15 GeV 2 < Q 2 < 20 GeV 2 and 20 GeV < < 420 GeV. The data were obtained in the Fermilab xed-target experiment E665 with primary muons of 470 GeV energy. Results are presented on the Q 2 , x and dependence of the cross section, on the shape of the + ? mass spectrum, on the slope of the diiraction peak and on the production and decay angular distributions of the 0 (770). The cross section for diiractive production of 0 by virtual photons on protons depends mainly on Q 2. At xed Q 2 , no signiicant dependence on x or is observed. The extrapolation to Q 2 = 0 yields a photoproduction cross section of (10:30 0:33) b. The slope of the t 0 distribution has a value of (7:00:2) GeV ?2 , with a tendency to decrease as Q 2 increases. The production and decay angular distributions of the 0 depend strongly on Q 2 and are consistent with s-channel helicity conservation. The ratio R = L == T deduced from the decay angular distributions rises strongly with Q 2 , passing the value of 1 at Q 2 2 GeV 2 .

The E140X Collaboration 3b R G. Arnold,l A. Banerjee4 A. Bodek,6 P. E. Bosted,l L. H. Tm,l L. Andivahis,l” P. L. Anthony, . J. Button-Shafer,4 S. Dmu,7c P. de Barbaro,6 F. S. Dietrich,3 J. Dunne,l M. Frodyma,g R. Gearhart,7 J. Gomez,2 K A Grifioen,5d R. A. Hicks,4 C, Hyde-Wright,ge C. Keppel,lf S. E. Kuhn,8e A. Lung,19 G. A. Peterson,4 G. G: Petratos,6h M. Rlordan,7 S. E. Rock,l S. %kni,7 M. Spengos,l L. M. Stuart,3b Z. M. Szalata,l K. Van Bibber,3 R. Wdker,6i K. Wang,4 J. L. White,lb U. K. Yang6 1The American University, Washington, D. C. 20016 2CEBAF, Newport News, Vi~inia 23606 3Lawrence Livemore National LabomtoW, Livermom, California 94550 4 University of Massachusetts, Amherst, Massachusetts 01003 5 University of Penns~lvania, Philadelphia, Pennsylvania 19104 6 University of Rochester, Rochester, NY 14627 ‘Stanford Linear Accelemtor Center, Stanford, California 94309 sStanfod University, Stanford, California 94305 g University of Washington, Seattle, WA 98195

The diffractive production of ρ0(770 @#@) mesons in muon-proton interactions is studied in the kinematic region 0.15 GeV2 < Q2 < 20 GeV2 and 20 GeV < ? < 420 GeV. The data were obtained in the Fermilab fixed-target experiment E665 with primary muons of 470 GeV energy. Results are presented on the Q2, x and ? dependence of the cross section, on the shape of the ρ+ρt - mass spectrum, on the slope of the diffraction peak and on the production and decay angular distributions of the ρ0(770). The cross section for diffractive production of ρ0 by virtual photons on protons depends mainly on Q2. At fixed Q2, no significant dependence on x or ? is observed. The extrapolation to Q2 = 0 yields a photoproduction cross section of (10.30 ± 0.33) μb. The slope of the t′ distribution has a value of (7.0 ± 0.2) GeV−2, with a tendency to decrease as Q2 increases. The production and decay angular distributions of the ρ0 depend strongly on Q2 and are consistent with s-channel helicity conservation. The ratio R = σ l /σ t deduced from the decay angular distributions rises strongly with Q2, passing the value of 1 at Q2 ≈ 2 GeV2.

The proton and deuteron structure functions F{sub 2}{sup p} and F{sub 2}{sup d} measured in inelastic muon scattering with an average beam energy of 470 GeV. The data were taken at Fermilab experiment 665 during 1991-1992 using liquid hydrogen and deuterium targets. The F{sub 2} measurements are reported in the range 0.0008 < x < 0.6 and 0.2 < Q{sup 2} < 75 GeV{sup 2}. These are the first precise measurements of F{sub 2} in the low x and Q{sub 2} range of the data. The E665 data overlap in x with the HERA data, and there is a smooth connection in Q{sup 2} between the two data sets. At high Q{sup 2} the E665 measurements are consistent with QCD-evolved leading twist structure function models. The data are qualitatively described by structure function models incorporating the hadronic nature of the photon at low Q{sup 2}. The Q{sup 2} and the W dependence of the data measure the transition in the nature of the photon between a point-probe at high Q{sup 2} and a hadronic object at low Q{sup 2}.

We report new results on a precision measurement of the ratio$R=\sigma_L/\sigma_T$ from hydrogen, deuterium, and beryllium targets for deep inelastic electron scattering in the range $0.1 \leq x \leq 0.7$ and $0.5\leq Q^2 \leq 7$ (GeV/c)$^2.$ We find no measurable difference between $R^p$ and $R^d.$ Our results are consistent with, and more precise than, previous SLAC data. At high $x,$$R$ is somewhat larger than order$\alpha_s^2$ pQCD predictions, even when target mass effects are included.

The ratio of the deuteron to proton structure functions is measured at very small Bjorken $x$ (down to 1${0}^{--6}$) and for ${Q}^{2}>0.001$ Ge${\mathrm{V}}^{2}$ from scattering of 470 GeV muons on liquid hydrogen and deuterium targets. The ratio ${F}_{2}^{n}{/F}_{2}^{p}$ extracted from these measurements is found to be constant, at a value of $0.935\ifmmode\pm\else\textpm\fi{}0.008\ifmmode\pm\else\textpm\fi{}0.034$, for $x<0.01$. This result suggests the presence of nuclear shadowing effects in the deuteron. The dependence of the ratio on ${Q}^{2}$ is also examined; no significant variation is found.

Nuclear shadowing is observed in the per-nucleon cross sections of positive muons on carbon, calcium and lead as compared to deuterium. The data were taken by Fermilab experiment E665 using inelastically scattered muons of mean incident momentum 470 GeV/c. Cross-section ratios are presented in the kinematic region 0.0001<x Bj <0.56 and 0.1<Q2<80 GeV2. The data are consistent with no significant ν orQ2 dependence at fixedx Bj . Asx Bj decreases, the size of the shadowing effect, as well as itsA dependence, are found to approach the corresponding measurements in photoproduction.