Hiroo Mayuzumi

Hepatocyte growth factor treatment improves alveolarization in a newborn murine model of bronchopulmonary dysplasia.

Background: Bronchopulmonary dysplasia (BPD) is thought to be one form of developmental arrest of the lung. Hepatocyte growth factor (HGF) participates in normal lung growth and in lung regeneration. Objectives: The purpose of this study is to investigate whether HGF can improve alveolarization and attenuates functional abnormalities of a murine model of BPD induced by hyperoxia. Methods: Three-day-old CD-1 mice were exposed to 90% of oxygen or room air (control group) for 7 days. These animals were then kept in room air for the next 7 days. Recombinant human (rh) HGF (100 μg/g b.w., divided 3 times, rhHGF group) or vehicle (vehicle group) was administered intraperitoneally during hyperoxia. On day 17, the pulmonary function test and bronchial hyperresponsiveness (BHR) were examined. Mean linear intercepts (MLI) were measured as parameters of alveolarization. Cell renewal (on day 10) and vascularization of the lung were also evaluated. Results: Exposure to hyperoxia induced increased airway resistance and BHR. These animals showed a severely simplified alveolar structure, increased MLI, decreased cell renewal (16.1 ± 2.4 vs. 29.6 ± 2.4%, p < 0.05), and decreased vascularization (15.1 ± 0.3 vs. 18.4 ± 1.5 vessels/hpf, p < 0.05, vehicle vs. control group, respectively). rhHGF treatment during exposure to hyperoxia significantly reduced all of these changes (27.9 ± 1.7%, 18.2 ± 0.5 vessels/hpf for cell renewal and vascularization, respectively; all values are p < 0.05 against vehicle animals). Conclusion: HGF partially protects against the inhibition of alveolarization and improves functional abnormality in the hyperoxia-induced neonatal mice model of BPD.

Characteristic Features of Allergic Airway Inflammation in a Murine Model of Infantile Asthma

Background: The pathophysiology of infantile asthma may differ from that in older children or in adults, partly because of the different immune response depending upon maturation. In adult mice, the sensitizing dose of antigen is known to be critical to the polarized development of helper T cell subsets and allergic airway inflammation. We wanted to know the characteristics of allergic airway inflammation of infantile asthma by developing a murine model. Methods: BALB/C mice at different stages of maturation (juvenile: 3 days after birth; adult: 8 weeks of age) were sensitized with 10 or 1,000 µg ovalbumin (OVA) or vehicle. The animals were then challenged with aerosolized OVA or saline once a day during 6 consecutive days. After the final challenge, bronchial hyperresponsiveness (BHR), bronchoalveolar lavage fluid (BALF), histological changes in the airways and immunological status were examined. Results: In both juvenile and adult animals, sensitization with 10 µg OVA induced the T helper 2 response (elevated IL-4 and decreased IFN-γ levels). BHR, airway eosinophilia, the inflammatory cell infiltration, goblet cell metaplasia (GCM), and IgE antibody production were more prominent in animals given this dose than 1,000 µg OVA. Among these responses, GCM as well as BALF IL-4, and BHR were comparable between juvenile and adult animals, whereas other parameters were lower in juvenile animals, especially in those given 1,000 µg OVA. Conclusion: GCM and, consequently, airway mucus hypersecretion may be an important component of allergic airway inflammation in infantile asthma.

Age-Related Difference in the Persistency of Allergic Airway Inflammation and Bronchial Hyperresponsiveness in a Murine Model of Asthma

Aim: Asthmatic children are more likely to outgrow their symptoms than adult patients. Thus, we wanted to know whether there were any age-related differences in the time course of the allergic airway inflammation. Methods: BALB/C mice at different ages (young: 3 days after birth, and mature: 8 weeks of age) were sensitized with ovalbumin (OVA). Subsequently, animals were challenged with aerosolized OVA during 1, 2, 4 or 8 consecutive weeks. Bronchial hyperresponsiveness (BHR), serum IgE levels, the degrees of inflammatory cell infiltration (ICI) and goblet cell metaplasia (GCM) in the airways, and the number of eosinophils and cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. Results: At 1 week, airway inflammation and BHR occurred similarly between young and mature mice. However, BHR disappeared at 4 weeks in young, whereas it persisted even at 8 weeks in mature mice. GCM, ICI and eosinophilia in BALF attenuated with time, with more remarkable reduction in young mice. The BALF IL-4 level was high during the first 2 weeks in both groups, while the IL-2 level was significantly increased at 2 weeks solely in young mice. Conclusion: Different time courses in airway inflammation and in BHR may relate to the different prognoses between childhood and adult asthma. The understanding of the mechanisms underlying this age-related differences may be helpful to induce remission in asthmatic patients.

Effect of Disodium Cromoglycate on Airway Mucus Secretion during Antigen-Induced Late Asthmatic Responses in a Murine Model of Asthma

Background: Disodium cromoglycate (DSCG) is known to inhibit both immediate and late asthmatic responses (IAR and LAR). However, its effect on mucus hypersecretion is unknown. Using a murine model of asthma, we aimed to determine whether mucus secretion increased during IAR and LAR. We also studied the potency of DSCG in inhibiting mucus secretion and on airway eosinophilia. Methods: Mice were subjected to initial intraperitoneal sensitizationand airway challenge to ovalbumin (OVA) and then provokedby additional exposure to OVA. Some mice were pretreated with aerosolized DSCG (20 mg/ml) 1 h before the provocation with OVA. After serial measurements of enhanced pause (Penh), an indicator of airflow obstruction, serum samples and bronchoalveolar lavage fluids (BALF) were collected. Then, the lungs were excised and a morphometric analysis for mucus hypersecretion was performed. Results: A biphasic increase in Penh (IAR and LAR) was observed in sensitized animals after provocation with OVA. Airway eosinophilia was observed during both responses. Intraluminal mucus significantly increased during LAR, but not during IAR. DSCG significantly attenuated both IAR and LAR, and significantly inhibited the increase in intraluminal mucus during LAR, but had no effect on eosinophilia in BALF. Conclusion: Our results suggest that airway hypersecretion may be involved as a component of airflow obstruction during LAR, and that this is unlikely during IAR. DSCG may be effective in reducing excessive airway mucus caused by exposure to allergens.

Periventricular Echodensity Measured with the Integrated Backscatter System: From a Qualitative Assessment to a Quantitative Approach

Background: The degree of periventricular white matter echodensity in preterm infants has been utilized as a sign of the early ultrasonographic appearance of periventricular leukomalacia, and this has been called periventricular echodensity (PVE). Objectives: The aim of this study was to quantitatively measure PVE utilizing a new method which is called calibrated integrated backscatter (calibrated IB). Methods: Eighty-eight preterm infants (extremely low birth weight infants, n = 17; very low birth weight infants, n = 26; low birth weight infants, n = 45) without any CNS abnormality were enrolled. IB is the returned sound pressure against supersonic waves sent from an ultrasonographic machine. The IB of the choroid plexus and periventricular white matter in the subrolandic area were measured on a parasagittal cerebral image. The degree of PVE was defined by subtracting the IB of the choroid plexus from that of the periventricular white matter in the subrolandic area (calibrated IB of PVE). Results: The intraobserver and interobserver correlations were both excellent (between 0.87 and 0.98 as correlation coefficients). There was a trend for the calibrated IB of PVE to decrease in accordance with time after birth, with a significant difference in very low birth weight and low birth weight infants. Conclusions: The objectively measured brightness of PVE was comparable to that of the choroid plexus irrespective of the size of the infants. Measurement of the calibrated IB of PVE might be a reliable method to assess PVE.

Contents Vol. 95, 2009

S. Andersson, Helsinki E. Bancalari, Miami, Fla. G. Buonocore, Siena W.A. Carlo, Birmingham, Ala. V.P. Carnielli, Ancona W.J. Cashore, Providence, R.I. I.A. Choonara, Derby T. Curstedt, Stockholm O. Dammann, Boston, Mass. C. Dani, Florence B. Darlow, Christchurch P. Gluckman, Auckland M. Hallman, Oulu B. Jonsson, Stockholm S.E. Juul, Seattle, Wash. A. Llanos, Santiago R.J. Martin, Cleveland, Ohio C.J. Morley, Cambridge J. Neu, Gainesville, Fla. P.C. Ng, Hong Kong M. Obladen, Berlin A.G.S. Philip, Palo Alto, Calif. M. Post, Toronto E. Saliba, Tours O.D. Saugstad, Oslo B. Schmidt, Philadelphia, Pa. E. Shinwell, Rehovot J. Smith, Cape Town B. Sun, Shanghai H. Togari, Nagoya F. van Bel, Utrecht N. Vain, Buenos Aires M. Vento Torres, Valencia M. Weindling, Liverpool J.A. Widness, Iowa City, Iowa Fetal and Neonatal Research

Contents Vol. 96, 2009

S. Andersson, Helsinki E. Bancalari, Miami, Fla. G. Buonocore, Siena W. Carlo, Birmingham, Ala. V.P. Carnielli, Ancona W.J. Cashore, Providence, R.I. I. Choonara, Derby T. Curstedt, Stockholm O. Dammann, Boston, Mass. C. Dani, Florence B. Darlow, Christchurch P.D. Gluckman, Auckland M. Hallman, Oulu B. Jonsson, Stockholm S.E. Juul, Seattle, Wash. A.J. Llanos, Santiago R.J. Martin, Cleveland, Ohio C.J. Morley, Cambridge J. Neu, Gainesville, Fla. P.C. Ng, Hong Kong M.W. Obladen, Berlin A.G.S. Philip, Sebastopol, Calif. M. Post, Toronto E. Saliba, Tours O.D. Saugstad, Oslo B. Schmidt, Philadelphia, Pa. E.S. Shinwell, Rehovot J. Smith, Tygerberg B. Sun, Shanghai H. Togari, Nagoya F. van Bel, Utrecht N. Vain, Buenos Aires M. Vento Torres, Valencia M. Weindling, Liverpool J.A. Widness, Iowa City, Iowa Fetal and Neonatal Research