Kenny Y.C. Kwong

Undetectable interleukin (IL)-10 and persistent IL-8 expression early in hyaline membrane disease: a possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns.

We are interested in determining whether premature birth alters expression of counterregulatory cytokines which modulate lung inflammation. Production of proinflammatory cytokines tumor necrosis factor α, IL-1β, and IL-8 is regulated in part by the antiinflammatory cytokine IL-10. For preterm newborns with hyaline membrane disease, deficiencies in the ability of lung macrophages to express antiinflammatory cytokines may predispose to chronic lung inflammation. We compared the expression of pro- and antiinflammatory cytokines at the mRNA and protein level in the lungs of preterm and term newborns with acute respiratory failure from hyaline membrane disease or meconium aspiration syndrome. Four sequential bronchoalveolar lavage (BAL) samples were obtained during the first 96 h of life from all patients. All patients rapidly developed an influx of neutrophils and macrophages. Over time, cell populations in both groups became relatively enriched with macrophages. The expression of proinflammatory cytokine mRNA and/or protein was present in all samples from both patient groups. In contrast, IL-10 mRNA was undetectable in most of the cell samples from preterm infants and present in the majority of cell samples from term infants. IL-10 concentrations were undetectable in lavage fluid from preterm infants with higher levels in a few of the BAL samples from term infants. These studies demonstrate that1) IL-10 mRNA and protein expression by lung inflammatory cells is related to gestational age and 2) during the first 96 h of life neutrophil cell counts and IL-8 expression decrease in BAL from term infants, but remain unchanged in BAL samples from preterm infants.

Ability to control persistent asthma in obese versus non-obese children enrolled in an asthma-specific disease management program (breathmobile).

To determine if asthma control was more difficult to achieve in obese versus non-obese asthmatic children, retrospective analysis was performed on obese and non-obese Los Angeles inner-city children (2 to 18 years of age) with persistent asthma. No difference in time required to achieve control of asthma, ability to maintain control of asthma, baseline pulmonary functions, and number of controllers prescribed was found between the two groups. We conclude that in a Los Angeles inner-city pediatric population, obesity is not a factor in the ability to control asthma.

Mesodermal Deletion of Transforming Growth Factor-β Receptor II Disrupts Lung Epithelial Morphogenesis: CROSS-TALK BETWEEN TGF-β AND SONIC HEDGEHOG PATHWAYS*

In vertebrates, Sonic hedgehog (Shh) and transforming growth factor-beta (TGF-beta) signaling pathways occur in an overlapping manner in many morphogenetic processes. In vitro data indicate that the two pathways may interact. Whether such interactions occur during embryonic development remains unknown. Using embryonic lung morphogenesis as a model, we generated transgenic mice in which exon 2 of the TbetaRII gene, which encodes the type II TGF-beta receptor, was deleted via a mesodermal-specific Cre. Mesodermal-specific deletion of TbetaRII (TbetaRII(Delta/Delta)) resulted in embryonic lethality. The lungs showed abnormalities in both number and shape of cartilage in trachea and bronchi. In the lung parenchyma, where epithelial-mesenchymal interactions are critical for normal development, deletion of mesenchymal TbetaRII caused abnormalities in epithelial morphogenesis. Failure in normal epithelial branching morphogenesis in the TbetaRII(Delta/Delta) lungs caused cystic airway malformations. Interruption of the TbetaRII locus in the lung mesenchyme increased mRNA for Patched and Gli-1, two downstream targets of Shh signaling, without alterations in Shh ligand levels produced in the epithelium. Therefore, we conclude that TbetaRII-mediated signaling in the lung mesenchyme modulates transduction of Shh signaling that originates from the epithelium. To our knowledge, this is the first in vivo evidence for a reciprocal and novel mode of cross-communication between Shh and TGF-beta pathways during embryonic development.In vertebrates, Sonic hedgehog (Shh) and transforming growth factor-β (TGF-β) signaling pathways occur in an overlapping manner in many morphogenetic processes. In vitro data indicate that the two pathways may interact. Whether such interactions occur during embryonic development remains unknown. Using embryonic lung morphogenesis as a model, we generated transgenic mice in which exon 2 of the TβRII gene, which encodes the type II TGF-β receptor, was deleted via a mesodermal-specific Cre. Mesodermal-specific deletion of TβRII (TβRIIΔ/Δ) resulted in embryonic lethality. The lungs showed abnormalities in both number and shape of cartilage in trachea and bronchi. In the lung parenchyma, where epithelial-mesenchymal interactions are critical for normal development, deletion of mesenchymal TβRII caused abnormalities in epithelial morphogenesis. Failure in normal epithelial branching morphogenesis in the TβRIIΔ/Δ lungs caused cystic airway malformations. Interruption of the TβRII locus in the lung mesenchyme increased mRNA for Patched and Gli-1, two downstream targets of Shh signaling, without alterations in Shh ligand levels produced in the epithelium. Therefore, we conclude that TβRII-mediated signaling in the lung mesenchyme modulates transduction of Shh signaling that originates from the epithelium. To our knowledge, this is the first in vivo evidence for a reciprocal and novel mode of cross-communication between Shh and TGF-β pathways during embryonic development.

Asthma control and future asthma-related morbidity in inner-city asthmatic children

BACKGROUND Asthma guidelines recommend routine evaluation of asthma control, which includes measurements of impairment and risk. It is unclear whether rigorous asthma control changes risk of asthma morbidity. OBJECTIVE To examine whether the degree of asthma control in inner-city asthmatic children results in differential risk reduction of future asthma-related morbidity. METHODS This retrospective observational study examines 960 inner-city children with asthma who were highly engaged in an asthma-specific disease management program for a minimum of 2 years. Degree of asthma control was determined during the first year of enrollment and was categorized as well controlled (> or = 80% of visits in control), moderately controlled (50%-79% of visits in control), or difficult to control (< 50% of visits in control). Risk and probability of asthma-related morbidity at each visit were determined during the second year of enrollment and included self-reported asthma exacerbations requiring systemic corticosteroid rescue and emergency department visits or hospitalizations. RESULTS Increasing the degree of asthma control measured during the first year of enrollment led to statistically significant incremental reductions in risk of acute asthma exacerbations and emergency department visits or hospitalizations during the second year of enrollment. CONCLUSIONS Achieving and maintaining asthma control in inner-city children with asthma results in significant reductions in asthma-related morbidity. Systematic assessments of asthma control may be useful for predicting future risk in children with asthma.

Constitutive IL-10 expression by lung inflammatory cells and risk for bronchopulmonary dysplasia.

Expression of IL-10 is decreased in lungs of preterm infants. We determined the constitutive and lipopolysaccharide (LPS)-induced IL-10 synthesis by lung inflammatory cells from preterm and term infants and examined their relationship to gestational age and/or incidence of bronchopulmonary dysplasia (BPD). A total of 37 infants; preterm neonates at gestational ages of 23–27 wk (group 1); 28–34 wk (group 2), and four full-term infants with meconium aspiration (group 3) were enrolled. One sample of lung inflammatory cells, obtained during postnatal d 1–3, and another during postnatal d 4–7 were cultured in vitro in presence or absence of 100 μg/mL of LPS. Secreted IL-10 was measured by ELISA. A positive relationship was found between gestational age and LPS-induced, but not constitutive IL-10 production within 1–3 d of life; group 1 on d 1–3 had a significant number of IL-10 nonresponders compared with group 2. All term neonates in group 3 had positive LPS-induced IL-10 response. Thus, in utero maturation of IL-10 gene expression is due to acquisition of inducibility. In contrast, constitutive IL-10 production within d 1–3 of life correlated with, and predicted the incidence of BPD in the highly vulnerable very premature infants.

Validation of a single survey that can be used for case identification and assessment of asthma control: the Breathmobile Program.

BACKGROUND Underdiagnosis of asthma and underrecognition of disease severity in lower socioeconomic populations continue to be significant health care concerns despite national efforts to better educate health care providers. OBJECTIVE To validate a 1-page survey as a point-in-time tool identifying uncontrolled vs controlled asthma and moderate-to-severe disease activity in an urban, lower-socioeconomic pediatric population. METHODS A previously validated survey (the Breathmobile Case Identification Survey) was evaluated as a point-in-time tool for identifying children with poorly controlled disease. Clinical validation was achieved in children (n = 1,826) presenting to a school-based asthma program for either an initial (n = 666) or a follow-up (n = 1,170) visit. Responses were compared with a comprehensive evaluation by a physician specialist as the gold standard. Response patterns were used to construct multimodel tiered scoring algorithms for baseline and follow-up visits that identify children with uncontrolled asthma, and children are likely to have moderate-to-severe disease activity at that time. RESULTS Surveys scored using the developed algorithms identified children with uncontrolled asthma (sensitivity: baseline, 77.0%; follow-up, 71.6%; specificity: baseline, 72.7%; follow-up, 71.5%) and detected moderate-to-severe disease activity (sensitivity: baseline, 69.2%; follow-up, 77.4%; specificity: baseline, 70.2%; follow-up, 70.3%). CONCLUSIONS The Breathmobile Case Identification Survey can be used in lower-socioeconomic, urban populations as a point-in-time tool for identifying children with uncontrolled vs controlled asthma and moderate-to-severe disease activity.

Improvement of asthma control with omalizumab in 2 obese pediatric asthma patients

BACKGROUND Dosing of the anti-IgE antibody (omalizumab) in the treatment of allergic asthma depends on serum IgE concentration and body weight. It is unclear whether omalizumab is therapeutically effective in obese patients with difficult-to-control asthma whose body weights fall outside dosing guidelines. OBJECTIVE To report the efficacy of omalizumab in 2 obese pediatric patients with severe persistent asthma whose high body weights placed them outside current dosing guidelines. METHODS Omalizumab was given at maximum doses to both patients. Standard asthma therapy was continued throughout the treatment period. Multiple parameters of asthma disease activity were followed at every health encounter for approximately 1 year during and before omalizumab treatment. These parameters included asthma disease severity and activity, pulmonary functions, daily inhaled corticosteroid requirements, systemic steroid rescue, and urgent care and emergency department visits and hospitalizations. RESULTS While receiving omalizumab, both patients had improvements in asthma disease activity and reduction in systemic steroid requirements. One patient required fewer daily inhaled corticosteroids and achieved total asthma control. CONCLUSION Patients with difficult-to-treat asthma may benefit from receiving omalizumab even if they fall outside current dosing guidelines because of high body weight.

Longitudinal Patterns of Predominant Asthma Disease Activity in Pediatric Patients Enrolled in an Asthma-Specific Disease Management Program

To determine if patterns of predominant asthma disease activity are more closely related than baseline asthma severity to measures of morbidity (acute asthma attack, emergency room visit/hospitalization, missed school days, and/or steroid burst). Retrospective analysis was performed for inner-city Los Angeles asthmatic children (3 to 18 years of age) during their first year of enrollment in an asthma-specific disease management program. All measures of morbidity were more closely related to patterns of predominant disease activity than baseline severity. We conclude that patterns of predominant disease activity are a more significant predictor of asthma morbidity than is baseline severity.

Asthma control and need for future asthma controller therapy among inner-city Hispanic asthmatic children engaged in a pediatric asthma disease management program (the Breathmobile program, Mobile Asthma Care for Kids Network)

Abstract Objective: To determine whether significant numbers of asthmatic children with initially rated intermittent asthma later suffer poor asthma control and require the addition of controller medications. Methods: Inner-city Hispanic children were followed prospectively in an asthma-specific disease management system (Breathmobile) for a period of 2 years. Clinical asthma symptoms, morbidity treatment, and demographic data were collected at each visit. Treatment was based upon National Heart, Lung, and Blood Institute (NHLBI) Expert Panel Report 3 asthma guidelines. Primary outcome was percentage of patients with intermittent asthma who had not well or poorly controlled asthma during subsequent visits and required controller agents. Secondary outcomes were factors associated with the maintenance of asthma control. Results: About 30.9% of the patients with initial rating of intermittent asthma had not well controlled and poorly controlled asthma during subsequent visits and required the addition of controller agents. Factors associated with good asthma control were compliance, no previous emergency room visits and previous visit during spring season. Conclusion: Asthmatic children with intermittent asthma often lose asthma control and require controller therapy. This justifies asthma guideline recommendations to assess asthma control at follow-up visits and adjust therapy accordingly.

TGFβ BIOACTIVITY AND ITS RELATIONSHIP WITH INFLAMMATION IN THE LUNGS OF PRETERM NEWBORNS WITH HYALINE MEMBRANE DISEASE. † 2009

TGFβ BIOACTIVITY AND ITS RELATIONSHIP WITH INFLAMMATION IN THE LUNGS OF PRETERM NEWBORNS WITH HYALINE MEMBRANE DISEASE. † 2009