Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An unadecapeptide, obtained by papain digestion of denatured human alpha-1-proteinase inhibitor (alpha-1-PI), has been isolated and sequenced. The structure of this fragment overlaps with the NH2-terminal sequence of modified inhibitor (alpha-1-PI) prepared from dissociated complexes of alpha-1-PI with trypsin, chymotrypsin, and elastase. Furthermore, structural homology with the reactive centers of proteinase inhibitors from other sources is readily detectable. Methionine has been found to occupy the apparent P1 position in alpha-1-PI and the potential inactivation of the inhibitor by oxidation of this critical residue may be important in obtaining a biochemical link with the development of lung disease.
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PMID:Structural evidence for methionine at the reactive site of human alpha-1-proteinase inhibitor. 70 Dec 39

Since it is still uncertain whether moderate degrees of alpha1-antitrypsin deficiency predispose to the development of lung disease, data obtained from a stratified random sample of white households in Tucson, Arizona, consisting of 2586 subjects over five years of age, were analyzed. No relation was found between serum alpha1-antitrypsin levels, measured as trypsin inhibitory capacity, and ventilatory function, respiratory symptomatology, or frequency of diagnosed pulmonary diseases even among cigarette smokers. The data indicate that an intermediate level of alpha1-antitrypsin deficiency (i.e., inhibitory capacity between 20 and 62 per cent of the population's mean value) is not an important risk factor for the development of chronic obstructive lung diseases. The data militate strongly against the use of any quantitative determination of alpha1-antitrypsin as a test to identify subjects with moderate deficiency for the purpose of predicting later development of chronic respiratory disorders. The rate of severe deficiency is so low as to make population screening for such subjects impractical.
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PMID:A community study of the relation of alpha1-antitrypsin levels to obstructive lung diseases. 107 96

Cigarette smokers have an increased risk of chronic obstructive airways disease which has been attributed to a protease-antiprotease imbalance in the lung. The neutrophil is an important source of proteases as well as of myeloperoxidase, which oxidatively inactivates alpha-1-proteinase inhibitor (alpha-1-PI). The purpose of this study is to evaluate the protease-antiprotease imbalance hypothesis by measuring changes in peripheral blood components in a group of 110 young, male, asymptomatic smokers and an equal number of age-matched non-smokers. Significant (p = 0.001), but modest impairment of pulmonary function was observed in the smokers as measured by both forced expiratory spirometry and the single breath nitrogen test. A 35% increase (p = 0.0001) in peripheral blood leukocytes in smokers was attributable to increases in neutrophils (44%), lymphocytes (31%) and monocytes (23%). This increase in leukocyte count correlated significantly (p less than or equal to 0.01) with some of the more sensitive indicators of airway obstruction (FEV1/FVC, CV/VC, CC/TLC, and delta N2/L). Myeloperoxidase activity of neutrophils isolated from peripheral blood of smokers was 13% higher than in non-smokers, while elastase activity per neutrophil was apparently unaffected by smoking. In 50 subject pairs, elevations in serum alpha-1-PI concentrations in smokers (13.7%) were comparable to similar increases in trypsin (9.9%) and elastase (12.4%) inhibitory capacities. Expressed as nanomoles protease inhibited per nanomole of alpha-1-PI, the apparent functional activity of alpha-1-PI was unaltered by smoking. However, a lower, apparent functional activity of alpha-1-PI against trypsin and elastase was observed in both smokers and non-smokers with higher serum alpha-1-PI concentrations. Thus, in a population of young smokers, changes in leukocyte count, neutrophil lysosomal enzyme activities, and functional serum antiprotease activity appear to be consistent with the establishment of a protease-antiprotease imbalance. This imbalance may predispose these smokers to obstructive lung disease.
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PMID:Effect of smoking on peripheral blood leukocytes and serum antiproteases. 299 5

Ten patients with rheumatoid arthritis were evaluated by bronchoalveolar lavage. Five patients (group I) had interstitial lung disease by physiological and radiographic criteria, whereas five (group II) had no evidence of lung disease. Lavage fluid from four of the five group I patients contained an active collagenase which by inhibitory profile and substrate specificity appeared to be of neutrophil origin. None of the group II patients demonstrated lavage fluid collagenase. Treatment of lavage fluid with trypsin failed to uncover latent collagenase activity in either group, suggesting that the collagenase is present entirely in an active form. These findings parallel those observed in idiopathic pulmonary fibrosis and suggest a potential pathogenetic role for collagenase in rheumatoid interstitial lung disease.
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PMID:Neutrophil collagenase in rheumatoid interstitial lung disease. 303 Oct 3

Certain cell-free filtrates from broth cultures of Pseudomonas aeruginosa, Hemophilus influenzae and Streptococcus pneumoniae stimulate secretion of glycoconjugates by explants of guinea pig trachea. The stimulatory effect is not related to toxicity or damage to the respiratory mucosa, as well as could be determined by ultrastructural examination of the explants after exposure. Bacteria isolated from patients with a history of chronic obstructive lung disease (P aeruginosa from cystic fibrosis, H influenzae, and S pneumoniae from chronic bronchitis) do not demonstrate increased frequency of positive strains or greater stimulation of secretion than organisms isolated from other individuals. At least three stimulatory substances are found in cell-free filtrates of P aeruginosa. They appear to be proteins of molecular weight 60,000-100,000 as determined by gel filtration. Within the crude filtrate, they are relatively stable to heat, proteolysis, and storage at 4 C and in liquid nitrogen. The stimulatory activity is not lost upon subculture of the bacteria. When isolated from the filtrate by column chromatography, they become labile to heat and trypsin. Isolated active fractions show proteolytic activity coinciding with mucin-stimulating capacity, suggesting a relationship with Pseudomonas proteases. Stimulatory substances released by S pneumoniae and H influenzae appear to be different from those elaborated by Pseudomonas. They are extremely labile to heat and storage, and the capacity to stimulate secretion is lost on subculture. Preliminary gel filtration indicates the S pneumoniae stimulatory substance(s) is in a molecular weight range of 100,000-300,000 daltons, while that of H influenzae is between 50,000 and 200,000. The results suggest bacteria which chronically infect or colonize respiratory airways of individuals suffering from obstructive lung disease can elaborate extracellular product(s) capable of stimulating secretion of mucin. Thus, the bacteria themselves may contribute to local manifestations and, ultimately, to the pathogenesis of obstructive disease.
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PMID:Bacteria associated with obstructive pulmonary disease elaborate extracellular products that stimulate mucin secretion by explants of guinea pig airways. 309 81

The isolation and characterization of three protease inhibitors from tracheobronchial secretions are described. As starting material, pooled secretions from patients with tracheostomies was used. The isolation procedure consisted of precipitation with 3% perchloric acid (the major acid-stable inhibitors remain in solution), affinity chromatography on trypsin-Sepharose, and preparative zone electrophoresis. We found three distinct inhibitors. One was a basic protein with evidence of size and charge heterogeneity but immunologic homogeneity, Mr = 15,850 +/- 1200 daltons, 12,600 +/- 700, 6500 +/- 500. Two inhibitors were acidic proteins, Mr = 63,400 +/- 3200 (AI) and 19,960 +/- 1500 (AII) daltons. The basic inhibitor had tyrosine as the sole aminoterminal amino acid. For the two acidic inhibitors, an aminoterminus was not found. All three inhibitors contained neutral sugars and amino sugars but no sialic acid. They inhibit trypsin, chymotrypsin, and human granulocytic elastase. The two acidic inhibitors are immunologically related; they are apparently derived from serum ITI. Inhibitor AII originates from inhibitor AI, probably by limited proteolysis by several proteases. The concentration of the basic inhibitor in bronchial secretions of 42 patients with obstructive lung disease was 0.206 +/- 0.15 mg/ml.
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PMID:Protease inhibitors in tracheobronchial secretions. 618 75

The molecular structure and the serum levels of alpha 1-antitrypsin, the major antiprotease of human serum, are controlled by a series of codominant alleles at a single chromosomal locus, known as the Pi(protease-inhibitor) locus. The congenital deficiency of this inhibitor is known to be associated with the development of lung emphysema in early adulthood and chronic liver disease in childhood. Less frequent associations have been reported, such as rheumatoid arthritis, membranoproliferative glomerulonephritis and mosaicism for sex chromosomes. The identification of several suballeles of the Pi system, which was accomplished by means of a refinement of the isoelectric focusing technique, has promoted research concerning their possible pathogenic implications. The studies so far performed have often led to contradictory results, but nevertheless they strongly ascribe the property of controlling the quantitative levels of alpha 1-antitrypsin to certain M subtypes. Intermediate M3 subtype has recently been associated with the development of chronic obstructive lung disease in adulthood. Should this finding be confirmed by further evidence, a new approach to the prevention of lung disease could be considered, given that 30% of the individuals are carriers of the M3 suballele. In Italy, the incidence of congenital deficiency of alpha 1-trypsin appears to be greater in the northern regions, where 15-20 out of every 100,000 individuals are affected by the severe (ZZ) form of the deficiency.
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PMID:Serum protease inhibitory capacity. (Recent knowledge on alpha 1-antitrypsin deficiency). 629 Nov 23

The 4 diagnostic stages of Cystic Fibrosis (C.F.) will be dealt with: prenatal diagnosis, singling out of the heterozygotes, clinical diagnosis and finally, the instrumental confirmation with the sweat test. The techniques for the intra-uterine diagnosis and for singling out of the heterozygotes are still in the experimental stage and cannot yet be put to practical use. The BM test on meconium is, among the numerous neonatal screening, no doubt the most widely used because of its simplicity and low cost. However, our personal experience has confirmed the high incidence of false negative (60%) and of false positive responses (0.8 - 0.9%). This has brought about a reconsideration upon the usefulness of neonatal screenings and this goes for the most recent method based on the dosage of blood trypsin levels. Because of the many difficulties imposed by the neonatal screening, there is a trend towards alternative diagnostic route: the clinical diagnosis. One of the most important objective symptoms even if it may seem trivial, is the reduced ponderal growth: in our personal experience, 51% of patients when diagnosed presented with weight below 10th percentile. One of the most frequent clinical pictures in that of a severe obstructive pulmonary disease of the infant. The high incidence of CF (1 in 1,250 live births) and the high mortality rate in the first year of life (50% of patients die during their first year) indicate that CF weighs heavily on the infantile mortality due to lung disease considered globally. This holds true above all for the Emilia-Romagna region, where the infantile mortality due to lung disease has been drastically reduced. One of the most recently discovered clinical manifestations, more frequent in hot climates, is the metabolic alkalosis. There is then a long series of minor clinical signs which should make one suspect a CF: a few of these are prolapse of the rectum, nasal polyposis, the equivalent of meconium ileus, haemorrhagic symptoms due to hypoprothrombinemia etc. An instrumental confirmation, a sweat test carried out with the quantitative method according to Gibson and Cooke, must always follow each clinical suspect. Unfortunately, alternative methods (such as the Orion C1 electrode or the Medtherm conductivity method) which have very high margins of error are still too widely used, in Italy as well, and should be completely abandoned.
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PMID:[Diagnosis of cystic fibrosis]. 664 74

Individuals with serum alpha1-antitrypsin levels below 80 mg/dl are clearly at risk for the development of accelerated panacinar emphysema. One possible approach to the therapy of this disorder would be to raise serum levels of this major antiprotease to establish protease-antiprotease homeostasis within the lung parenchyma. Because danazol, an impeded androgen, elevates levels of C1 inhibitor in patients deficient of that serum antiprotease, we hypothesized that this agent might also increase alpha1-antitrypsin levels in patients with alpha1-antitrypsin deficiency. To evaluate this concept, seven patients with severe emphysema associated with alpha1-antitrypsin deficiency (six PiZ and 1 M(Duarte)Z) and one asymptomatic individual (PiSZ) received 600 mg of danazol daily for 30 d. Five of the six PiZ patients responded to danazol therapy with significant increases in serum alpha1-antitrypsin levels (mean increase of 37%; P < 0.03). The two individuals who were heterozygous for the Z protein increased their serum levels by 85% (PiM(Duarte)Z) and 87% (PiSZ), respectively. These increases in serum alpha1-antitrypsin antigen were accompanied by commensurate increases in serum trypsin inhibition. Crossed immunoelectrophoresis showed no alterations of the microheterogeneity of the alpha1-antitrypsin or the presence of protease-antiprotease complexes in serum during danazol therapy. These data demonstrate that serum alpha1-antitrypsin levels can be augmented by danazol therapy in PiZ individuals as well as those heterozygotes with severe deficiency of alpha1-antitrypsin. The clinical relevance of these increases in serum alpha1-antitrypsin remains speculative, but these findings suggest that danazol may provide a means of improving the protease-antiprotease balance in these individuals and thus impede the progression of their lung disease.
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PMID:Danazol-induced augmentation of serum alpha 1-antitrypsin levels in individuals with marked deficiency of this antiprotease. 696 89

Bronchopulmonary dysplasia (BPD), the most common cause of chronic lung disease in prematurely born infants, is histologically characterized by various degrees of airway and alveolar septal fibrosis. Tryptase, a serine protease specific to mast cells, has been shown to have potent fibroblast mitogenic properties and in addition has been shown to be increased in adult fibrotic lung disorders. Based on this analogy, the distribution of pulmonary mast cells exhibiting tryptase immunoreactivity was investigated by immunoperoxidase staining in autopsy specimens of infants dying with BPD. Morphologically normal lung specimens from similarly aged infants dying of sudden infant death syndrome (SIDS) served as controls. Tryptase-positive mast cell counts were performed at 250x from at least 10 random fields in bronchial, peribronchiolar, and alveolar regions. Compared to controls, in lung sections exhibiting typical histologic features of long-standing BPD, tryptase positive cells were significantly increased in bronchial (23.9 +/- 3.6 vs 14.4 +/- 2.3) and peribronchiolar (15.3 +/- 3.2 vs 4.63 +/- 0.6) regions compared to controls (P < 0.05, Student's t test). In particular, alveolar regions exhibiting moderate to severe degrees of septal fibrosis exhibited a dramatic increase in the number of tryptase-positive cells (9.83 +/- 1.89 vs 0.34 +/- 0.18, P = 0.003). These findings of a tryptase-positive mast cell hyperplasia in BPD suggest potential roles of mast cells as well as tryptase in the pathogenesis of this disease.
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PMID:Tryptase immunoreactive mast cell hyperplasia in bronchopulmonary dysplasia. 756 12


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