Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling Richard Leigh, MBChB, PhD, Wale.

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Presentation transcript:

Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling Richard Leigh, MBChB, PhD, Wale Oyelusi, BSc, Shahina Wiehler, MSc, Rommy Koetzler, MD, MSc, Raza S. Zaheer, BSc, Robert Newton, PhD, David Proud, PhD Journal of Allergy and Clinical Immunology Volume 121, Issue 5, Pages 1238-1245.e4 (May 2008) DOI: 10.1016/j.jaci.2008.01.067 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 HRV-16 infection (solid bars) significantly upregulated amphiregulin (A), activin A (B), and VEGF (C) protein production measured by means of ELISA compared with that seen in noninfected control subjects (open bars) in BEAS-2B and HBE cells. Data are presented as means ± SEM (n = 6-9). Journal of Allergy and Clinical Immunology 2008 121, 1238-1245.e4DOI: (10.1016/j.jaci.2008.01.067) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 VEGF isoforms visualized by means of agarose gel electrophoresis. Total cellular RNA was extracted from control and HRV-16–infected BEAS-2B cells and used to perform RT-PCR by using primers capable of detecting all known VEGF isoforms. A molecular weight marker is included on the left. Asterisks indicate the isoforms increased by HRV-16 infection. Data are representative of 2 experiments. Journal of Allergy and Clinical Immunology 2008 121, 1238-1245.e4DOI: (10.1016/j.jaci.2008.01.067) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Effects of selective inhibitors of the ERK1/2 (PD-98059 or U0126), p38 (SB-203580), or JNK (SP-600125) MAPK pathways on VEGF protein production in BEAS-2B (A) and primary HBE (B) cells after HRV-16 infection. Data are presented as means ± SEM (n = 4-6 per condition). Asterisks indicate significant inhibition (P < .05) compared with HRV-16 plus dimethyl sulfoxide (DMSO). Journal of Allergy and Clinical Immunology 2008 121, 1238-1245.e4DOI: (10.1016/j.jaci.2008.01.067) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 The small-molecule, highly selective IKKβ inhibitors PS-1145 (A and B) and ML-120B (C and D) each dose-dependently inhibit HRV-16–induced production of IL-8 from BEAS-2B epithelial cells but did not inhibit VEGF production (n = 3). Asterisks indicate significant inhibition (P < .05) compared with HRV-16 plus dimethyl sulfoxide (DMSO). Journal of Allergy and Clinical Immunology 2008 121, 1238-1245.e4DOI: (10.1016/j.jaci.2008.01.067) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Patient symptom scores recorded during the 3 consecutive days of the study were ranked as peak (day of maximal symptoms), mid, and low. Measurements were done on each patient at each time point. Peak symptoms scores were significantly correlated with the highest HRV viral titers (P < .001) and with maximal IP-10 protein levels (P < .001). TCID50, 50% Tissue culture-infective dose. Journal of Allergy and Clinical Immunology 2008 121, 1238-1245.e4DOI: (10.1016/j.jaci.2008.01.067) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Levels of VEGF protein in nasal lavage fluid from 26 subjects with natural HRV infections both at the time of peak symptoms and at baseline 4 weeks after symptom resolution. Horizontal bars represent mean values. Journal of Allergy and Clinical Immunology 2008 121, 1238-1245.e4DOI: (10.1016/j.jaci.2008.01.067) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

HRV -16 infection (solid bars) upregulated VEGF protein production in BEAS-2B cells in a time-dependent manner, with significant increases compared with levels in noninfected control subjects (open bars) first evident 8 hours and maximally evident 24 hours after infection. Data are presented as means ± SEMs (n = 4). NS, Not significant. Journal of Allergy and Clinical Immunology 2008 121, 1238-1245.e4DOI: (10.1016/j.jaci.2008.01.067) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Real -time RT-PCR analysis of VEGF mRNA in BEAS-2B cells at 1, 3, and 24 hours after HRV-16 infection indicate that maximal fold induction occurred 3 hours after infection. Data are expressed relative to appropriate controls. Data are presented as means ± SEMs (n = 4). Journal of Allergy and Clinical Immunology 2008 121, 1238-1245.e4DOI: (10.1016/j.jaci.2008.01.067) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

HRV -16 infection of BEAS-2B cells upregulated the ERK, p38, and JNK MAPK pathways in a time-dependent manner, with maximal induction occurring at approximately 30 to 60 minutes. Data are representative of 3 experiments. Journal of Allergy and Clinical Immunology 2008 121, 1238-1245.e4DOI: (10.1016/j.jaci.2008.01.067) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions