alpha-chymotrypsin and alpha-1-Antitrypsin-Deficiency

Topics: alpha 1-Antitrypsin Deficiency; alpha-Macroglobulins; Bronchitis; Chymotrypsin; Humans; Lung; Pancreatic Elastase; Pneumonia; Pulmonary Emphysema

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.

Topics: alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Animals; Chronic Disease; Chymotrypsin; Disease Models, Animal; Female; Fetal Development; Inflammation; Leukocyte Elastase; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Proteins; Serpins

Fractionated plasma alpha1-antitrypsin is widely-used as replacement therapy in patients with Z alpha1-antitrypsin deficiency-related emphysema. We have recently shown that purified antitrypsin may be induced to adopt an inactive latent conformation by heating at high temperatures in stabilizing concentrations of sodium citrate. Such a conformation was predicted to be present in commercial preparations of antitrypsin, as these require heating under similar conditions for viral inactivation. Native antitrypsin was purified from plasma, and commercial antitrypsin (Prolastin) was obtained from Bayer Corporation. Western blot analysis of transverse urea gradient (TUG) gels showed that commercial antitrypsin migrated as two bands: one with an unfolding profile of native antitrypsin and the second with a profile of latent antitrypsin. A latent fraction, comprising approximately 8% of the total antitrypsin, was separated from the native antitrypsin in Prolastin by anion exchange chromatography. The specific activity of this latent form against bovine alpha-chymotrypsin increased from 1 to 2% to 50% over 3 h after refolding from 6 M guanidine hydrochloride. These data show that commercial antitrypsin contains a latent component. The significance of this conformation in vivo is unknown, although Prolastin has shown few adverse side-effects in prolonged clinical usage.

Topics: alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Animals; Blotting, Western; Cattle; Chymotrypsin; Electrophoresis, Polyacrylamide Gel; Humans; Phenotype; Protein Conformation; Pulmonary Emphysema; Serine Proteinase Inhibitors

Topics: Adult; Aged; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Cholecystectomy; Cholecystitis; Chymotrypsin; Female; Humans; Laser Therapy; Middle Aged; Postoperative Complications; Prognosis; Safety; Trypsin

We studied 229 patients with biopsy verified liver disease and compared the plasma levels of alpha 1-antichymotrypsin and alpha 1-antitrypsin. We found a significant overall correlation between alpha 1-antichymotrypsin and alpha 1-antitrypsin levels (r = 0.50, p less than 0.001). The strongest correlations were found in patients with chronic active hepatitis (r = 0.76, p less than 0.0001) and alcohol hepatitis (r = 0.60, p less than 0.001). Several clinical subgroups lacked correlation. Unexpectedly high alpha 1-antichymotrypsin values were found in patients with venous congestion. We also used the alpha 1-antichymotrypsin/alpha 1-antitrypsin ratio as a tool to identify PiZ carriers (intermediate alpha 1-antitrypsin-deficiency, PiZ). The sensitivity and predictive values were low and did not exceed that obtained by the simple use of an isolated alpha 1-antitrypsin determination. A small subgroup with low alpha 1-antichymotrypsin/alpha 1-antitrypsin ratio included patients with chronic active hepatitis of unknown etiology. Hypo-alpha 1-antichymotrypsinemia may be secondary to the liver disease per se or be an expression of an abnormal genetic trait.

Topics: Adolescent; Adult; Aged; alpha 1-Antichymotrypsin; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Chymotrypsin; Female; Genetic Carrier Screening; Hepatitis, Alcoholic; Hepatitis, Chronic; Humans; Liver Diseases; Liver Diseases, Alcoholic; Male; Middle Aged; Phenotype

In protein-energy malnutrition essential amino acids for the synthesis of proteins are derived from the mobilization of endogenous proteins in order to maintain homoeostasis. Data are presented to support the hypothesis that proteinase inhibitors, which increase rapidly at the onset of infection, interrupt this catabolic effect which is the normal adaptive response to protein-energy malnutrition.

Topics: alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Amino Acids, Essential; Blood Proteins; Chymotrypsin; Homeostasis; Humans; Infant; Infant, Newborn; Protease Inhibitors; Protein-Energy Malnutrition

A group of 163 patients with chronic obstructive pulmonary disease, from the pulmonary service of a large urban hospital, were evaluated for their protease inhibitor (Pi) type by starch gel and crossed immunoelectrophoresis, for serum concentrations of alpha1-antitrypsin and alpha1-antichymotrypsin, and for pulmonary function. Of the patients with emphysema, 17.8% were of Pi type Z; 50% of these were less than 45 years of age, compared to 13% of those of Pi type M. Of all patients with chronic obstructive pulmonary disease, 4.9% were of Pi type Z; 4.9% of patients were of Pi type MZ (heterozygotes) compared with 1.9% of the control population. There was an increased incidence of chronic obstructive pulmonary disease in persons of Pi type MZ, but no increase in persons of Pi type MS. Concentrations of both alpha1-antitrypsin and alpha1-antichymotrypsin were increased and were correlated. No patient had a deficiency of alpha1-antichymotrypsin.

Topics: Adult; Aged; alpha 1-Antitrypsin Deficiency; Chymotrypsin; Female; Heterozygote; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Pulmonary Emphysema

In the bronchial mucus of 40 patients with chronic obstructive airway diseases we measured proteolytic activities, the total protein concentrations, alpha1-antitrypsin, alpha1-antichymotrypsin, and the free and bound proteinase inhibitors together with the total proteinase inhibition against trypsin and chymotrypsin. Without exception we always found free proteinase inhibitors together with proteolytic activities. The free-to-bound inhibitor rate was approximately 1:1 alpha1-Antitrypsin and alpha1-antichymotrypsin was measured in sputum only in very low concentrations. One patient with alpha1-anti-trypsin deficiency had no alpha1-antitrypsin, but high concentrations of total proteinase inhibitor-free and bound being in the same relation - in his bronchial mucus. In the alveolar part of the lung, the humoral proteinase inhibitors were effective. In the bronchial part of the lung the specific mucosal inhibitors had the decided importance. The proteinase inhibition of the mucosa-specific inhibitors is probably of great importance for the pathogenesis of airway obstruction, while the humoral proteinase inhibitors are responsible for the pathogenesis of emphysema.

Topics: Adult; Aged; alpha 1-Antitrypsin Deficiency; Bronchitis; Chymotrypsin; Humans; Middle Aged; Mucous Membrane; Mucus; Protease Inhibitors; Proteins; Pulmonary Emphysema; Sputum; Syndrome; Trypsin Inhibitors