Clinical practice. Alpha1-antitrypsin deficiency.

Channing Laboratory and Pulmonary and Critical Care Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
New England Journal of Medicine (Impact Factor: 54.42). 07/2009; 360(26):2749-57.
Source: PubMed
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    ABSTRACT: Inflammation is a central feature of stable chronic obstructive pulmonary disease (COPD) and involves both activation of structural cells of the airways and the lungs and the activation and/or recruitment of infiltrating inflammatory cells. This results in enhanced expression of many pro-inflammatory proteins and reduced expression of some anti-inflammatory mediators. An altered protein expression is generally associated with concomitant changes in gene expression profiles in a cell-specific manner. Increased understanding of the role of transcription factors and of the signaling pathways leading to their activation in stable COPD will provide new targets to enable the development of potential anti-inflammatory drugs. Several new compounds targeting these pathways and/or transcription factors are now in development for the treatment of stable COPD. Furthermore, glucocorticoids drugs already in clinical use act through their own transcription factor, the glucocorticoid receptor, to control the expression of inflammatory and anti-inflammatory genes.
    Annals of the New York Academy of Sciences 01/2015; 13401(1). DOI:10.1111/nyas.12619 · 4.31 Impact Factor
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    Tanaffos 01/2012; 11(1):71-2.
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    ABSTRACT: Human genome-wide association studies (GWASs) have identified numerous associations between single nucleotide polymorphisms (SNPs) and pulmonary function. Proving that there is a causal relationship be-tween GWAS SNPs, many of which are noncoding and without known functional impact, and these traits has been elusive. Furthermore, noncoding GWAS-identified SNPs may exert trans-regulatory effects rather than impact the proximal gene. Noncoding variants in 5-hydroxytrypta-mine (serotonin) receptor 4 (HTR4) are associated with pulmonary function in human GWASs. To gain insight into whether this association is causal, we tested whether Htr4-null mice have altered pulmonary function. We found that HTR4-deficient mice have 12% higher baseline lung re-sistance and also increased methacholine-induced airway hyperresponsiveness (AHR) as measured by lung resis-tance (27%), tissue resistance (48%), and tissue elastance (30%). Furthermore, Htr4-null mice were more sensitive to serotonin-induced AHR. In models of exposure to bac-terial lipopolysaccharide, bleomycin, and allergic airway inflammation induced by house dust mites, pulmonary function and cytokine profiles in Htr4-null mice differed little from their wild-type controls. The findings of altered baseline lung function and increased AHR in Htr4-null mice support a causal relationship between genetic var-iation in HTR4 and pulmonary function identified in human GWAS.—House,. Genetic variation in HTR4 and lung function: GWAS follow-up in mouse. FASEB J. 29, 000–000 (2015). Key Words: pulmonary function • airway hyperresponsiveness • mouse models
    The FASEB Journal 10/2014; 29(1). DOI:10.1096/fj.14-253898 · 5.48 Impact Factor