Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are genetic and exogenous factors responsible for alpha 1-antitrypsin (alpha 1-AT) deficiency which may lead to cirrhosis of the liver and emphysema. The present study was initiated on a biochemical level in order to determine whether acetaldehyde, the major product of ethanol metabolism, is capable of influencing the physiological effect of alpha 1-AT upon elastase, an enzyme which is capable of inducing emphysema. The effects of acetaldehyde and ethanol upon elastase and alpha 1-AT were tested. Acetaldehyde at 0.3-M and 1.2-M concentrations inhibited the anti-elastase activity of alpha 1-AT. Acetaldehyde at 0.03-M and 0.07-M concentrations did not affect elastase activity and had a slight effect at 0.12-M levels. Equivalent amounts of ethanol were without influence upon elastase activity or alpha 1-AT function. These data provide biochemical support for the possibility that heterozygous males with lower than normal alpha 1-AT levels may be at much higher risk to develop liver disease, emphysema, and alpha 1-AT deficiency as a consequence of chronic exposure to ethanol and concomitant circulating acetaldehyde levels.
 ...
PMID:Acetaldehyde inhibits the anti-elastase activity of alpha 1-antitrypsin. 806 May 17

Alpha-1-antitrypsin (alpha1-AT) is a member of the serine protease inhibitor family regulating numerous proteolytic processes. The genetic disorder, alpha1-AT deficiency, is well known as a cause of hereditary pulmonary emphysema and liver cirrhosis. To create an animal model of human alpha1-AT deficiency, we disrupted the major murine isoform PI2, which is similar to human alpha1-AT and is one of 7 alpha1-AT isoforms found in the mouse. The ability of the serum to inhibit the activities of human leukocyte elastase (HLE) and human chymotrypsin (CYT) was significantly lower in heterozygous mice (alpha1-AT/PI2 -/+) than wild-type (alpha1-AT/PI2 +/+) mice (73.2% vs. 100% for HLE and 67.8% vs.100% for CYT, respectively; P<0.05). The distribution of genotypes among F(2) progeny was not in accordance with Mendelian distribution (P<0.01), as the percentages of wild-type, heterozygotes and homozygotes were 47.8%, 37.3% and 14.9%, respectively. Thus, it is likely that impairment of the protease inhibitor had a critical effect on fetus development. The alpha1-AT/PI2 deficient mouse will be a useful animal model for elucidating the function of alpha1-AT in fetal development, studying the mechanisms of chronic inflammatory disease and evaluating therapeutic candidates for the treatment of inflammatory disease.
 ...
PMID:Disruption of the murine alpha1-antitrypsin/PI2 gene. 1551 92

The molecular mechanisms that cause emphysema are complex but most theories suggest that an excess of proteinases is a crucial requirement. This paradigm is exemplified by severe deficiency of the key anti-elastase within the lung: alpha(1)-antitrypsin. The Z mutant of alpha(1)-antitrypsin has a point mutation Glu342Lys in the hinge region of the molecule that renders it prone to intermolecular linkage and loop-sheet polymerization. Polymers of Z alpha(1)-antitrypsin aggregate within the liver leading to juvenile liver cirrhosis and the resultant plasma deficiency predisposes to premature emphysema. We show here that polymeric alpha(1)-anti-trypsin co-localizes with neutrophils in the alveoli of individuals with Z alpha(1)-antitrypsin-related emphysema. The significance of this finding is underscored by the excess of neutrophils in these individuals and the demonstration that polymers cause an influx of neutrophils when instilled into murine lungs. Polymers exert their effect directly on neutrophils rather than via inflammatory cytokines. These data provide an explanation for the accelerated tissue destruction that is characteristic of Z alpha(1)-antitrypsin-related emphysema. The transition of native Z alpha(1)-antitrypsin to polymers inactivates its anti-proteinase function, and also converts it to a proinflammatory stimulus. These findings may also explain the progression of emphysema in some individuals despite alpha(1)-antitrypsin replacement therapy.
 ...
PMID:Polymers of Z alpha1-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo. 1568 22