Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The granule-associated elastase homologues neutrophil elastase (NE), proteinase 3 (PR3), and azurocidin (AZU) are involved in immune defense reactions of neutrophils and monocytes. Proteinase 3 and NE contribute to the destruction and elimination of microorganisms, cleave elastin and other proteins of connective tissues, and generate chemotactic activities by forming alpha 1-proteinase inhibitor (alpha 1-PI) complexes. Azurocidin is cytotoxic to certain microorganisms and chemotactic to monocytes. All three proteins are produced and packaged into azurophil granules in large quantities during neutrophil development. The genes encoding AZU, PR3, and NE are closely clustered in this sequence within 50 kb of genomic DNA and have the same transcriptional orientation. All three genes show the same exon-intron organization as neutrophil cathepsin G, mast cell chymase 1, and the lymphocyte serine proteases, granzymes A, B, and H. The AZU-PR3-NE gene cluster was mapped to the telomeric region on the short arm of human chromosome 19 (19p13.3), whereas cathepsin G, lymphocyte granzymes B and H, and mast cell chymase 1 are organized as a separate gene cluster on chromosome 14q11.2. Neutrophil-derived serine proteases are widely regarded as pathogenic factors in degenerative and inflammatory diseases with abnormal tissue catabolism. Autoantibodies against PR3 are an obligate feature in the pathogenesis of Wegener's granulomatosis, a systemic autoimmune vasculitis. In addition, PR3 appears to regulate growth and terminal differentiation of the myelomonocyte lineage. Future investigations will clarify whether allelic variations in the AZU-PR3-NE locus predispose patients to increased degradation of elastic fibers, as in pulmonary emphysema, and to the formation of autoantibodies against PR3 in patients with Wegener's granulomatosis.
 ...
PMID:Structure of the azurocidin, proteinase 3, and neutrophil elastase genes. Implications for inflammation and vasculitis. 795 51

Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.
...
PMID:Telomere dysfunction causes alveolar stem cell failure. 2584 May 90

Lung cellular senescence and inflammatory response are the key events in the pathogenesis of chronic obstructive pulmonary disease (COPD) when cigarette smoke (CS) is the main etiological factor. Telomere dysfunction is induced by either critical shortening or disruption of the shelterin complex, leading to cellular senescence. However, it remains unknown whether disruption of the shelterin complex is responsible for CS-induced lung cellular senescence. Here we show that telomere protection protein 1 (TPP1) levels are reduced on telomeres in lungs from mice with emphysema, as well as in lungs from smokers and from patients with COPD. This is associated with persistent telomeric DNA damage, leading to cellular senescence. CS disrupts the interaction of TPP1 with the Sirtuin 1 (Sirt1) complex, leading to increased TPP1 acetylation and degradation. Lung fibroblasts deficient in Sirt1 or treated with a selective Sirt1 inhibitor exhibit increased cellular senescence and decreased TPP1 levels, whereas Sirt1 overexpression and pharmacological activation protect against CS-induced TPP1 reduction and telomeric DNA damage. Our findings support an essential role of TPP1 in protecting CS-induced telomeric DNA damage and cellular senescence, and therefore provide a rationale for a potential therapy for COPD, on the basis of the shelterin complex, in attenuating cellular senescence.
 ...
PMID:Shelterin Telomere Protection Protein 1 Reduction Causes Telomere Attrition and Cellular Senescence via Sirtuin 1 Deacetylase in Chronic Obstructive Pulmonary Disease. 2755 27