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1.  Cell Therapy for Lung Diseases. Report from an NIH–NHLBI Workshop, November 13–14, 2012 
The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened the Cell Therapy for Lung Disease Working Group on November 13–14, 2012, to review and formulate recommendations for future research directions. The workshop brought together investigators studying basic mechanisms and the roles of cell therapy in preclinical models of lung injury and pulmonary vascular disease, with clinical trial experts in cell therapy for cardiovascular diseases and experts from the NHLBI Production Assistance for Cell Therapy program. The purpose of the workshop was to discuss the current status of basic investigations in lung cell therapy, to identify some of the scientific gaps in current knowledge regarding the potential roles and mechanisms of cell therapy in the treatment of lung diseases, and to develop recommendations to the NHLBI and the research community on scientific priorities and practical steps that would lead to first-in-human trials of lung cell therapy.
doi:10.1164/rccm.201303-0522WS
PMCID: PMC3778734  PMID: 23713908
mesenchymal stromal (stem) cells; epithelial and endothelial progenitor cells; lung stem cells
2.  Cell Plasticity in Lung Injury and Repair 
In April 2010, a NIH workshop was convened to discuss the current state of understanding of lung cell plasticity, including the responses of epithelial cells to injury, with the objectives of summarizing what is known, what the field needs to know, and how to get there. The proximal stimulus for this workshop is the body of recent evidence suggesting that plasticity is a prominent but incompletely characterized property of lung epithelial cells, and that a focus on understanding this aspect of epithelial cell biology in particular, may be an important window into disease pathobiology and pathogenesis. In addition to their many vital functions in maintaining tissue homeostasis, epithelial cells have emerged as both a central target of disease initiation and an active contributor to disease progression, making a workshop to investigate the role of cell plasticity in lung injury and repair timely. The workshop was organized around four major themes: lung epithelial cell plasticity, signaling control of plasticity, fibroblast plasticity and crosstalk, and translation to human disease. Although this breakdown was recognized to be somewhat artificial, it was felt that this approach would promote cross-fertilization among groups that ordinarily do not communicate and lend itself to the generation of new approaches. The summary reports of individual group discussions below are followed by consensus priorities and recommendations of the workshop participants.
doi:10.1513/pats.201012-067CB
PMCID: PMC3132783  PMID: 21653526
epithelial-mesenchymal transition (EMT); idiopathic pulmonary fibrosis; cell lineage
3.  Developmental Aspects of the Upper Airway 
The upper airway serves three important functions: respiration, swallowing, and speech. During development it undergoes significant structural and functional changes that affect its size, shape, and mechanical properties. Abnormalities of the upper airway require prompt attention, because these often alter ventilatory patterns and gas exchange, particularly during sleep when upper airway motor tone and ventilatory drive are diminished. Recognizing the relationship of early life events to lung health and disease, the National Heart, Lung, and Blood Institute (NHLBI), with cofunding from the Office of Rare Diseases (ORD), convened a workshop of extramural experts, from many disciplines. The objective of the workshop was: (1) to review the state of science in pediatric upper airway disorders; (2) to make recommendations to the Institute to fill knowledge gaps; (3) to prioritize new research directions; and (4) to capitalize on scientific opportunities. This report provides recommendations that could facilitate translation of basic research findings into practice to better diagnose, treat, and prevent airway compromise in children.
doi:10.1513/pats.200905-024CB
PMCID: PMC3136952  PMID: 19741259
4.  Molecular Determinants of Lung Development 
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.
doi:10.1513/AnnalsATS.201207-036OT
PMCID: PMC3955361  PMID: 23607856
lung development; lung cell fate; lung cell differentiation; tissue interaction; environmental impact
5.  Molecular Determinants of Lung Development 
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.
doi:10.1513/AnnalsATS.201207-036OT
PMCID: PMC3955361  PMID: 23607856
lung development; lung cell fate; lung cell differentiation; tissue interaction; environmental impact
6.  National Heart, Lung, and Blood Institute Perspective: Lung Progenitor and Stem Cells—Gaps in Knowledge and Future Opportunities 
Stem Cells (Dayton, Ohio)  2009;27(9):2263-2270.
Because the lung stem cell field is so new, there remain many unanswered questions that are being addressed regarding the identification, location, and role of exogenous and endogenous stem and progenitor cell populations in growth, regeneration, and repair of the lung. Advancing lung stem cell biology will require multidisciplinary teams and a long term effort to unravel the biologic processes of stem cells in the lung. While no clinical research in lung stem cell therapies are currently funded by NHLBI, the knowledge gained by understanding the basic biology of the lung stem cell populations will be needed to translate to diagnostic and therapeutic strategies in the future.
doi:10.1002/stem.148
PMCID: PMC2962803  PMID: 19522010
Lung cell biology; Lung regeneration; Reprogramming
7.  Improving Outcomes for Pulmonary Vascular Disease 
Recognizing the importance of improving lung health through lung disease research, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of multidisciplinary experts for the following purpose: (1) to review the current scientific knowledge underlying the basis for treatment of adults and children with pulmonary vascular diseases (PVDs); (2) to identify gaps, barriers, and emerging scientific opportunities in translational PVD research and the means to capitalize on these opportunities; (3) to prioritize new research directions that would be expected to affect the clinical course of PVDs; and (4) to make recommendations to the NHLBI on how to fill identified gaps in adult and pediatric PVD clinical research. Workshop participants reviewed experiences from previous PVD clinical trials and ongoing clinical research networks with other lung disorders, including acute respiratory distress syndrome, chronic obstructive lung disease, and idiopathic pulmonary fibrosis, as well. Bioinformatics experts discussed strategies for applying cutting-edge health information technology to clinical studies. Participants in the workshop considered approaches in the following broad concept areas: (1) improved phenotyping to identify potential subjects for appropriate PVD clinical studies; (2) identification of potential new end points for assessing key outcomes and developing better-designed PVD clinical trials; and (3) the establishment of priorities for specific clinical research needed to advance care of patients with various subsets of PVDs from childhood through adulthood. This report provides a summary of the objectives and recommendations to the NHLBI concentrating on clinical research efforts that are needed to better diagnose and treat PVDs.
doi:10.1164/rccm.201201-0049WS
PMCID: PMC3359939  PMID: 22335936
clinical trials; pediatrics; pulmonary hypertension; pulmonary vascular changes
8.  Elevated Ambient Air Zinc Increases Pediatric Asthma Morbidity 
Environmental Health Perspectives  2008;116(6):826-831.
Background
Recent studies indicate that the composition of fine particulate matter [PM ≤ 2.5 μm in aerodynamic diameter (PM2.5)] is associated with increased hospitalizations for cardiovascular and respiratory diseases. The metal composition of PM2.5 influences allergic and/or inflammatory reactions, and ambient zinc contributes to worsening pulmonary function in susceptible adults. However, information is limited concerning associations between ambient air zinc levels and health care utilization for asthma, especially among children.
Objective
We aimed to investigate the relationship between outdoor ambient air PM2.5 zinc levels and urgent health care utilization for children living in an urban area.
Methods
We used a time-series study to estimate the association of ambient air PM2.5 zinc levels with hospital admissions and emergency department (ED) utilization by children in Baltimore, Maryland, controlling for time trends. We used data from daily discharge administrative claims of ED and hospital utilization for asthma in children, 0–17 years of age for Greater Baltimore from June 2002 through November 2002. We collected ambient air PM2.5 metal concentration data, determined by X-ray fluorescence spectroscopy, during the U.S. Environmental Protection Agency–sponsored Baltimore Supersite project.
Results
Previous-day medium levels of zinc (8.63–20.76 ng/m3) are associated with risks of pediatric asthma exacerbations that are 1.23 (95% confidence interval, 1.07–1.41) times higher than those with previous-day low levels of zinc (< 8.63 ng/m3) after accounting for time-varying potential confounders.
Conclusion
Results suggest that high ambient air PM2.5 zinc levels are associated with an increase in ED visits/hospital admissions for asthma on the following day among children living in an urban area.
doi:10.1289/ehp.10759
PMCID: PMC2430241  PMID: 18560541
air pollution; asthma; children; emergency departments; hospitals; zinc
9.  Management of acute asthma exacerbations by general practitioners: a cross-sectional observational survey 
Background: General practitioners (GPs) have a central place in the management of asthma, particularly in the context of acute exacerbations.
Aim: To evaluate the management of asthma exacerbations by GPs, and to investigate the ability of risk factors for near fatal asthma to predict the severity of asthma attacks in the community.
Design of study: A 1-month multicentre cross-sectional survey.
Setting: One thousand and ninety-four GPs of the French Sentinel Network were contacted; 365 responded.
Methods: Asthma exacerbations were classified according to severity at presentation. Univariate and multivariate analyses were performed by logistic regression to identify those factors associated with severe exacerbations.
Results: Exacerbations were described in 219 patients with asthma. Over half (54%) of exacerbations were severe. Peak expiratory flow was recorded during the consultation in 55% of patients who were more than 5 years old. ß2 agonists were prescribed to 93% of patients, systemic corticosteroids to 71%, and antibiotics to 64%. Only 42% of patients had a written action plan for self-management of exacerbations. Risk factors for near fatal asthma, identified in 26% of patients, were not significantly associated with severe asthma exacerbations. Short duration of exacerbation before consultation (<3 hours) was associated with an increase in relative risk of severe exacerbation of 3.38, 95% confidence intervals (CIs) = 1.19 to 9.61, compared with duration of >3 hours.
Conclusion: Risk factors for near fatal asthma identified in previous studies were not predictive of a severe exacerbation in general practice, with the exception of short duration of exacerbation before consultation. This suggests that new methods to predict risk in the outpatient settings should be developed.
PMCID: PMC1324881  PMID: 15469675
Asthma; general practitioners; patient care management; risk factors
10.  CLC-2 single nucleotide polymorphisms (SNPs) as potential modifiers of cystic fibrosis disease severity 
BMC Medical Genetics  2004;5:26.
Background
Cystic fibrosis (CF) lung disease manifest by impaired chloride secretion leads to eventual respiratory failure. Candidate genes that may modify CF lung disease severity include alternative chloride channels. The objectives of this study are to identify single nucleotide polymorphisms (SNPs) in the airway epithelial chloride channel, CLC-2, and correlate these polymorphisms with CF lung disease.
Methods
The CLC-2 promoter, intron 1 and exon 20 were examined for SNPs in adult CF dF508/dF508 homozygotes with mild and severe lung disease (forced expiratory volume at one second (FEV1) > 70% and < 40%).
Results
PCR amplification of genomic CLC-2 and sequence analysis revealed 1 polymorphism in the hClC -2 promoter, 4 in intron 1, and none in exon 20. Fisher's analysis within this data set, did not demonstrate a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene.
Conclusions
CLC-2 is not a key modifier gene of CF lung phenotype. Further studies evaluating other phenotypes associated with CF may be useful in the future to assess the ability of CLC-2 to modify CF disease severity.
doi:10.1186/1471-2350-5-26
PMCID: PMC526769  PMID: 15507145

Results 1-10 (10)