American journal of respiratory cell and molecular biology
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Am. J. Respir. Cell Mol. Biol. · Sep 2009
Transforming growth factor-beta receptor-3 is associated with pulmonary emphysema.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, including emphysema and airway disease. Phenotypes defined on the basis of chest computed tomography (CT) may decrease disease heterogeneity and aid in the identification of candidate genes for COPD subtypes. To identify these genes, we performed genome-wide linkage analysis in extended pedigrees from the Boston Early-Onset COPD Study, stratified by emphysema status (defined by chest CT scans) of the probands, followed by genetic association analysis of positional candidate genes. ⋯ Gene-level replication of association with lung function was seen in 427 patients with COPD from the Lung Health Study. In conclusion, stratified linkage analysis followed by association testing identified TGFBR3 (betaglycan) as a potential susceptibility gene for COPD. Published human microarray and murine linkage studies have also demonstrated the importance of TGFBR3 in emphysema and lung function, and our group and others have previously found association of COPD-related traits with TGFB1, a ligand for TGFBR3.
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Am. J. Respir. Cell Mol. Biol. · May 2009
A critical role of SHP-1 in regulation of type 2 inflammation in the lung.
Asthma is a chronic inflammatory disorder of the airways. Type 2 T helper (Th) cell-dominated inflammation in the lung is a hallmark of asthma. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 is a negative regulator in the signaling pathways of many growth factor and cytokine receptors. ⋯ The pulmonary phenotype was accompanied by up-regulation of Th2 cytokines and chemokines. Selective deletion of IL-13 or signal transducer and activator of transcription 6, key genes in the Th2 signaling pathway, significantly reduced, but did not completely eliminate, the inflammation in the lung. These findings suggest that SHP-1 plays a critical role in regulating the IL-4/IL-13 signaling pathway and in maintaining lung homeostasis.
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Am. J. Respir. Cell Mol. Biol. · May 2009
ReviewTransepithelial migration of neutrophils: mechanisms and implications for acute lung injury.
The primary function of neutrophils in host defense is to contain and eradicate invading microbial pathogens. This is achieved through a series of swift and highly coordinated responses culminating in ingestion (phagocytosis) and killing of invading microbes. While these tasks are usually performed without injury to host tissues, in pathologic circumstances such as sepsis, potent antimicrobial compounds can be released extracellularly, inducing a spectrum of responses in host cells ranging from activation to injury and death. ⋯ Herein, we review the mechanisms involved in the physiologic process of neutrophil transepithelial migration, including the role of specific adhesion molecules on the leukocyte and epithelial cells. We examine the responses of the epithelial cells to the itinerant leukocytes and their cytotoxic products and the consequences of this for lung injury and repair. This paradigm has important clinical implications because of the potential for selective blockade of these pathways to prevent or attenuate lung injury.
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Am. J. Respir. Cell Mol. Biol. · Apr 2009
Promotion of lung carcinogenesis by chronic obstructive pulmonary disease-like airway inflammation in a K-ras-induced mouse model.
Lung cancer is the leading cause of cancer deaths in the United States. In addition to genetic abnormalities induced by cigarette smoke, several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lungs, have an increased risk of lung cancer (1.3- to 4.9-fold) compared to smokers without COPD. This suggests a link between chronic airway inflammation and lung carcinogenesis, independent of tobacco smoke exposure. ⋯ Lung lesions in CCSP(Cre-Neo)/LSL-K-ras(G12D) and CCSP(Cre)/LSL-K-ras(G12D) mice appeared at 4 and 1 month of age, respectively, and were classified as epithelial hyperplasia of the bronchioles, adenoma, and adenocarcinoma. Weekly exposure of CCSP(Cre)/LSL-K-ras(G12D) mice to aerosolized nontypeable Haemophilus influenzae lysate from age 6-14 weeks resulted in neutrophil/macrophage/CD8 T-cell-associated COPD-like airway inflammation, a 3.2-fold increase in lung surface tumor number (156 +/- 9 versus 45 +/- 7), and an increase in total lung tumor burden. We conclude that COPD-like airway inflammation promotes lung carcinogenesis in a background of a G12D-activated K-ras allele in airway secretory cells.
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Am. J. Respir. Cell Mol. Biol. · Mar 2009
Activation of peroxisome proliferator-activated receptor beta/delta induces lung cancer growth via peroxisome proliferator-activated receptor coactivator gamma-1alpha.
We previously demonstrated that a selective agonist of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta), GW501516, stimulated human non-small cell lung carcinoma (NSCLC) growth, partly through inhibition of phosphatase and tensin homolog deleted on chromosome 10 expression. Here, we show that GW501516 also decreases the phosphorylation of AMP-activated protein kinase alpha (AMPKalpha), a major regulator of energy metabolism. This was mediated through specific activation of PPARbeta/delta, as a PPARbeta/delta small interfering RNA inhibited the effect. ⋯ An inhibitor of PI3-K, LY294002, had no effect on PGC-1alpha, consistent with PGC-1alpha being upstream of PI3-K/Akt. Of note, an activator of AMPKalpha, 5-amino-4-imidazole carboxamide riboside, inhibited the growth-promoting effects of GW501516, suggesting that although AMPKalpha is not responsible for the mitogenic effects of GW501516, its activation can oppose these events. This study unveils a novel mechanism by which GW501516 and activation of PPARbeta/delta stimulate human lung carcinoma cell proliferation, and suggests that activation of AMPKalpha may oppose this effect.