Disease relevance of Emphysema

• Three case definitions of COPD were used: symptoms of chronic bronchitis (667 subjects), physician-diagnosed emphysema reported by the subject (185 subjects), and spirometrically detected COPD (197 subjects) [1].
• To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome [2].
• Through a global analysis of pulmonary gene expression in the lungs of mice lacking this integrin (Itgb6 null mice) we have identified a marked induction of macrophage metalloelastase (Mmp12)--a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema [3].
• Besides emphysema, HLE may also contribute to the pathogenesis of disease states such as adult respiratory distress syndrome, and its potential involvement in rheumatoid arthritis makes HLE inhibitors of considerable interest [4].
• A deficiency in the plasma protease inhibitor alpha 1-antitrypsin can cause chronic obstructive emphysema or infantile liver cirrhosis [5].

Psychiatry related information on Emphysema

• Stratification of patients into those with and without macroscopic emphysema (EMPH+, EMPH-, respectively), with comparable physical activity levels on the basis of previous observations, revealed lower values for La threshold and GLU in EMPH+ patients [6].
• We believe that the issue of neonatal screening for alpha 1-antitrypsin deficiency should be reexamined because augmentation therapy for adults with emphysema is now available, and screening followed by family-based smoking intervention may lead to a nonsmoking life-style [7].
• This is the first reported case of isolated retropharyngeal emphysema caused by ingestion of the amphetamine derivatives "Ecstasy" and "Speed". The same complication has been reported with marihuana, cocaine, and heroin abuse [8].

High impact information on Emphysema

• Pulmonary function may improve after surgical resection of the most severely affected lung tissue (lung-reduction surgery) in patients with diffuse emphysema [9].
• Although elastase has been proposed as the primary enzyme responsible for emphysematous lung damage, this study provides evidence that other extracellular matrix proteases could play a role in emphysema [10].
• This pathology is strikingly similar to the morphological changes observed in human emphysema and therefore implicates interstitial collagenase as a possible etiological agent in the disease process [10].
• Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema [11].
• Finally, increased lung ceramides in individuals with smoking-induced emphysema suggests that ceramide upregulation may be a crucial pathogenic element and a promising target in this disease that currently lacks effective therapies [12].

Chemical compound and disease context of Emphysema

• Treatment with all-trans-retinoic acid reversed these changes providing nonsurgical remediation of emphysema and suggesting the possibility of a similar effect in humans [13].
• Emphysema was reproduced with intratracheal instillation of ceramide in naive mice [12].
• Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema [3].
• The present study appears to offer a plausible explanation for the emphysema that occurs in industrial workers exposed to cadmium [14].
• Monensin and the prevention of tryptophan-induced acute bovine pulmonary edema and emphysema [15].

Biological context of Emphysema

• We report that ceramide, a second messenger lipid, is a crucial mediator of alveolar destruction in emphysema [12].
• Thus, macrophage elastase is probably sufficient for the development of emphysema that results from chronic inhalation of cigarette smoke [16].
• These findings suggest that VEGF receptor signaling is required for maintenance of the alveolar structures and, further, that alveolar septal cell apoptosis contributes to the pathogenesis of emphysema [17].
• Although inflammation and protease/antiprotease imbalance have been postulated to be critical in cigarette smoke-induced (CS-induced) emphysema, oxidative stress has been suspected to play an important role in chronic obstructive pulmonary diseases [18].
• The alpha 1AT haplotype S is associated with childhood liver disease and/or adult emphysema when inherited with the Z haplotype to give the phenotype SZ [19].

Anatomical context of Emphysema

• Increased elastase derived from pulmonary neutrophils, rather than decreased functional alpha 1-protease inhibitor, appears to be the main factor in the genesis of emphysema in smokers [20].
• Since enzymes that digest elastin produce pulmonary emphysema in experimental animals, release of elastase by alveolar macrophages from smokers suggests that these cells are important in the pathogenesis of emphysema of smokers [21].
• After degradation by macrophage elastase, alpha 1-proteinase inhibitor is no longer able to inhibit human granulocyte elastase, a serine proteinase implicated in the pathogenesis of emphysema [22].
• Mice lacking macrophage elastase (matrix metalloproteinase-12, or MMP-12) were previously shown to be protected from the development of cigarette smoke-induced emphysema and from the accumulation of lung macrophages normally induced by chronic exposure to cigarette smoke [23].
• The Tight skin (Tsk) mutation is a duplication of the mouse fibrillin 1 (Fbn1) gene that results in a larger (418 kD) than normal (350 kD) protein; Tsk/+ mice display increased connective tissue, bone overgrowth, and lung emphysema [24].

Gene context of Emphysema

• Here we report that Itgb6-null mice develop age-related emphysema that is completely abrogated either by transgenic expression of versions of the beta6 integrin subunit that support TGF-beta activation, or by the loss of Mmp12 [3].
• IFN-gamma causes emphysema and alterations in pulmonary protease/antiprotease balance when expressed in pulmonary tissues [25].
• Role of CCR5 in IFN-gamma-induced and cigarette smoke-induced emphysema [26].
• Targeted ablation of the surfactant protein D (SP-D) gene caused chronic inflammation, emphysema, and fibrosis in the lungs of SP-D (-/-) mice [27].
• These results suggest that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema, a chronic pulmonary disease that often leads to formation of bullous lesions and lowered pulmonary function [28].

Analytical, diagnostic and therapeutic context of Emphysema

• Intravenous infusion of 250 mg/kg of alpha 1AT at 28-day intervals to nine individuals with alpha 1AT deficiency and emphysema was carried out for 12 months [29].
• Interestingly, transplantation of wild-type bone marrow cells into Nrf2-KO mice retarded the development of initial lung inflammation and subsequent emphysema, and this improvement correlated well with the appearance of macrophages expressing Nrf2-regulated antiprotease and antioxidant genes [30].
• Excessive neutrophil elastase in bronchoalveolar lavage fluid in subclinical emphysema [31].
• This hypothesis was tested in a clinical study by comparing EP concentration in male emphysematous patients with the level in two control groups, and by exploring the relation of elastin peptide level to high-resolution computed tomography (HRCT) scan emphysema score among emphysematous patients [32].
• Immunohistochemistry studies localized MMP-1 to the Type II pneumocyte in patients with emphysema and not normal control subjects or smokers without emphysema [33].

References