American journal of respiratory cell and molecular biology
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Am. J. Respir. Cell Mol. Biol. · Aug 2019
ReviewOmics and the Search for Blood Biomarkers in Chronic Obstructive Pulmonary Disease. Insights from COPDGene.
There is an unmet need for blood biomarkers in diagnosis and prognosis of chronic obstructive pulmonary disease (COPD). The search for these biomarkers has been revolutionized by high-throughput sequencing techniques and multiplex platforms that can measure thousands of gene transcripts, proteins, or metabolites. We review COPDGene (Genetic Epidemiology of COPD) project publications that include DNA methylation, transcriptomic, proteomic, and metabolomic blood biomarkers and discuss their impact on COPD. ⋯ Genes, proteins, and metabolite networks are particularly important because the explanatory value of any single molecule is small (1-10%) compared with panels of multiple markers. COPDGene has been a useful resource in the identification and validation of multiple biomarkers for COPD. These biomarkers, either combined in multiple biomarker panels or integrated with other omics data types, may lead to novel diagnostic and prognostic tests for COPD phenotypes and may be relevant for assessing novel therapies.
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Am. J. Respir. Cell Mol. Biol. · Aug 2019
Prolonged Cold Ischemia Induces Necroptotic Cell Death in Ischemia-Reperfusion Injury and Contributes to Primary Graft Dysfunction after Lung Transplantation.
Primary graft dysfunction (PGD) is a major cause of morbidity and mortality after lung transplantation. Ischemia-reperfusion injury (IRI) is a key event that contributes to PGD, though complex interactions affect donor lungs status, such as preceding brain death (BD), hemorrhagic shock (HS), and pre-engraftment lung management, the latter recognized as important risk factors for PGD. We hypothesized that a multi-hit isogenic mouse model of lung transplantation is more closely linked to PGD than IRI alone. ⋯ Thus, activation of necroptosis is a central event in IRI after prolonged CI, though it may not be sufficient to cause PGD alone. Pathological evaluation of donor lungs after CI-induced IRI, in conjunction with pre-engraftment donor lung factors in our multi-hit model, demonstrated early evidence of lung injury consistent with PGD. Our findings support the premise that pre-existing donor lung status is more important than CI time alone for inflammatory pathway activation in PGD, which may have important clinical implications for donor lung retrieval.
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Am. J. Respir. Cell Mol. Biol. · May 2019
Randomized Controlled TrialGenome-Wide Association Analysis of Single-Breath DlCO.
DlCO is a widely used pulmonary function test in clinical practice and a particularly useful measure for assessing patients with chronic obstructive pulmonary disease (COPD). We hypothesized that elucidating genetic determinants of DlCO could lead to better understanding of the genetic architecture of COPD. We estimated the heritability of DlCO using common genetic variants and performed genome-wide association analyses in four cohorts enriched for subjects with COPD (COPDGene [Genetic Epidemiology of COPD], NETT [National Emphysema Treatment Trial], GenKOLS [Genetics of Chronic Obstructive Lung Disease study], and TESRA [Treatment of Emphysema With a Gamma-Selective Retinoid Agonist study]) using a combined European ancestry white dataset and a COPDGene African American dataset. ⋯ Among 25 previously reported COPD loci, TGFB2, CHRNA3/CHRNA5, FAM13A, DSP, and CYP2A6 were associated with DlCO (P < 0.001). We identified several genetic loci that were significantly associated with DlCO and characterized effects of known COPD-associated loci on DlCO. These results could lead to better understanding of the heterogeneous nature of COPD.
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Am. J. Respir. Cell Mol. Biol. · Feb 2019
P311 Promotes Lung Fibrosis via Stimulation of Transforming Growth Factor-β1, -β2, and -β3 Translation.
Interstitial lung fibrosis, a frequently idiopathic and fatal disease, has been linked to the increased expression of profibrotic transforming growth factor (TGF)-βs. P311 is an RNA-binding protein that stimulates TGF-β1, -β2, and -β3 translation in several cell types through its interaction with the eukaryotic translation initiation factor 3b. We report that P311 is switched on in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and in the mouse model of bleomycin (BLM)-induced pulmonary fibrosis. ⋯ Furthermore, treatment of BLM-exposed P311 knockouts with recombinant TGF-β1, -β2, and -β3 induced pulmonary fibrosis to a degree similar to that found in BLM-treated wild-type mice. These studies demonstrate the essential function of P311 in TGF-β-mediated lung fibrosis. Targeting P311 could prove efficacious in ameliorating the severity of IPF while circumventing the development of autoimmune complications and toxicities associated with the use of global TGF-β inhibitors.
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Am. J. Respir. Cell Mol. Biol. · Jan 2019
Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis In Vivo.
Although cellular senescence may be a protective mechanism in modulating proliferative capacity, fibroblast senescence is now recognized as a key pathogenic mechanism in idiopathic pulmonary fibrosis (IPF). In aged mice, abundance and persistence of apoptosis-resistant senescent fibroblasts play a central role in nonresolving lung fibrosis after bleomycin challenge. Therefore, we investigated whether quercetin can restore the susceptibility of senescent IPF fibroblasts to proapoptotic stimuli and mitigate bleomycin-induced pulmonary fibrosis in aged mice. ⋯ In vivo quercetin reversed bleomycin-induced pulmonary fibrosis and attenuated lethality, weight loss, and the expression of pulmonary senescence markers p21 and p19-ARF and senescence-associated secretory phenotype in aged mice. Collectively, these data indicate that quercetin reverses the resistance to death ligand-induced apoptosis by promoting FasL receptor and caveolin-1 expression and inhibiting AKT activation, thus mitigating the progression of established pulmonary fibrosis in aged mice. Therefore, quercetin may be a viable therapeutic option for IPF and other age-related diseases that progress with the accumulation of senescent fibroblasts.