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The tight-skin (Tsk) mouse is a model of genetically determined emphysema. The cause for the development of the lung lesion is unknown. In the present study we investigated the lung morphometry and the serum elastase inhibitory capacity (EIC) of Tsk mice. Mean interalveolar distance was significantly greater (+60%) in Tsk mice than in C57 Bl/6J, NMRI, and Balb/c mice, which have similar values. Serum of Tsk mice against mouse leukocyte elastase (MLE) has significantly lower EIC values than that of NMRI, Balb/c (-64%), and C57 Bl/6J (-50%) mice. Similar results were obtained when porcine pancreatic elastase (PPE) was used. Against human leukocyte elastase (HLE), however, there was no difference among the strains, all of which had high EIC values. Preincubation of mouse (C57 Bl/6J) serum with chloramine-T (CT) resulted in an almost complete inhibition of EIC against MLE and PPE but only in a 20% inhibition against HLE using a synthetic substrate. Using elastin Congo Red as substrate, CT inhibited EIC against MLE and PPE by approximately 70% but did not affect the EIC against HLE. These results indicate that (1) the Tsk mouse can be considered a model of severe inborn deficiency of serum antielastase activity which is associated with emphysema; and (2) MLE and PPE can be considered interchangeable in studies of serum EIC in the mouse. On the other hand, the differences between MLE and HLE preclude the use of HLE for EIC determination in this species.
Exp Mol Pathol 1990 Feb
PMID:Serum antielastase deficiency in tight-skin mice with genetic emphysema. 230 13

Hamsters exposed to an intratracheal instillation of human neutrophil elastase (HNE) accumulate an abnormally high number of secretory granules in bronchial but not tracheal epithelial cells. We employed lectin cytochemistry to investigate possible differences in the epithelial cell surface glycoconjugate layer in trachea compared to bronchus which might explain the regional dissimilarity in response to HNE. Portions of glutaraldehyde-fixed trachea and bronchi were incubated in one of several ferritin-labeled lectins prior to embedding for transmission electron microscopy. Lectins from Ricinus communis, Helix pomatia, and Triticum vulgaris bound to the surface of tracheal secretory cells in moderate to profuse amounts, while most bronchial secretory cells showed little or no label with these lectins. Gold-labeled Helix pomatia agglutinin (HPA), a lectin specific for secretory cells, showed a decrease in surface binding to all tracheal secretory cell types within 2 h of HNE instillation, compared to saline controls. In contrast, the majority of bronchial secretory cells showed an HNE-induced increase in surface label from extremely low levels in saline controls. The low levels of lectin binding to bronchial cells, in contrast to the trachea, may indicate the lack of a protective surface glycoconjugate coat, thus explaining the vulnerability of these cells to HNE. The rise in number of accessible HPA binding sites on the surface of bronchial secretory cells exposed to HNE may represent an important event in the pathologic accumulation of secretory granules by these cells.
Am J Respir Cell Mol Biol 1990 Jul
PMID:Lectin cytochemistry reveals differences between hamster trachea and bronchus in the composition of epithelial surface glycoconjugates and in the response of secretory cells to neutrophil elastase. 236 36

The two major protease inhibitors in mouse plasma are alpha 1-protease inhibitor (alpha 1-PI), putative inhibitor of neutrophil elastase, and contrapsin, an inhibitor in vitro of trypsinlike proteases. We have shown by nucleotide sequence analysis that these two inhibitors are related (R. E. Hill, P. H. Shaw, P. A. Boyd, H. Baumann, and N. D. Hastie, Nature (London) 311:175-177, 1984). Here, we show that the contrapsin and alpha 1-PI genes are members of two different multigene families, each containing at least three genes in mice and rats. We established the chromosomal locations of these genes by analyzing the segregation of restriction fragment length polymorphisms in recombinant inbred mouse strains. These experiments show that the multiple genes in each family are clustered and that the two gene families are closely linked on chromosome 12. Thus the genes for contrapsin and alpha 1-PI are likely to have evolved by duplication of a common ancestral gene. The contrapsin multigene family codes for multiple mRNA transcripts in the liver. There is a genetic difference among inbred mouse strains in the regulation of two of these transcripts. In some inbred strains the transcripts are synthesized constitutively; in others they are induced by inflammation. We mapped in recombinant inbred strains the regulatory locus responsible for this genetic variation and found it is linked to the contrapsin multigene family, which suggests a cis-acting regulatory element. We also found that the contrapsin and the alpha 1-PI multigene families have acquired very different regulatory responses since the time of the gene duplication event.
Mol Cell Biol 1985 Aug
PMID:A genetic locus closely linked to a protease inhibitor gene complex controls the level of multiple RNA transcripts. 242 31

Pseudomonas aeruginosa, which may cause severe lung infections, secretes a metalloelastase that may interfere with the assay of neutrophil elastase and cathepsin G in lung secretions. Using nuclear magnetic resonance spectroscopy, we have shown that P. aeruginosa elastase (PsE) cleaves succinyl-Ala3-p-nitroanilide between the first and the second alanine residue, rendering this substrate inefficient for the assay of neutrophil elastase. The cleavage occurs with a kcat/Km of 2.4 X 10(3) M-1 s-1, a value eightfold higher than the kcat/Km for the chromogenic cleavage of succinyl-Ala3-p-nitroanilide by neutrophil elastase. P. aeruginosa elastase also cleaves the elastase substrate succinyl-Ala3-Val-p-nitroanilide between the second and the third alanine residue and the cathepsin G substrate succinyl-Ala2-Pro-Phe-p-nitroanilide at the Pro-Phe linkage. By contrast, methoxysuccinyl-Ala2-Pro-Val-p-nitroanilide, another elastase substrate, is not hydrolyzed by the bacterial enzyme. Our data indicate that synthetic substrates should be used with caution to assay elastase and cathepsin G in lung secretions or other biologic fluids in which metalloproteinases may be present.
Am J Respir Cell Mol Biol 1989 Jul
PMID:Nonchromogenic hydrolysis of elastase and cathepsin G p-nitroanilide substrates by Pseudomonas aeruginosa elastase. 251 50

Cigarette smoking may impair the lung antiprotease screen. To test this hypothesis, the lung lining fluid from 10 smoking and 9 nonsmoking individuals was evaluated for its ability to inhibit neutrophil elastase and porcine pancreatic elastase. To eliminate the possibility of concentration- or purification-induced artifact, unconcentrated bronchoalveolar lavage fluid was used for all experiments. Smokers did not differ significantly from nonsmokers in the antigenic alpha-1-antitrypsin (alpha 1AT) concentrations (0.67 +/- 0.04 versus 0.73 +/- 0.09 nmol alpha 1AT/mg protein), in the neutrophil elastase inhibitory capacity (NEIC) (0.59 +/- 0.03 versus 0.52 +/- 0.05 nmol NEIC/mg protein), or in the porcine pancreatic elastase inhibitory capacity (PPEIC) (0.36 +/- 0.03 versus 0.42 +/- 0.05 nmol PPEIC/mg protein). In contrast, when the PPEIC/NEIC ratio was evaluated, smoker lung lining fluid exhibited a relative defect (0.64 +/- 0.06 smokers versus 0.80 +/- 0.05 nonsmokers, P less than 0.05). In agreement with the smokers' defect in the PPEIC/NEIC ratio, the kinetics of association (Ka) of lung lining fluid for neutrophil elastase was 0.38 +/- 0.3 x 10(7) M-1 s-1 from smokers and 0.58 +/- 0.05 x 10(7) M-1 s-1 from nonsmokers (P less than 0.002). Thus for a given amount of neutrophil elastase, smoker lung lining fluid took approximately 1.5 times longer to inhibit neutrophil elastase. These findings suggest that cigarette smoking is associated with a subtle defect in the antiprotease screen of the lower respiratory tract, recognizable by time-dependent measures of anti-neutrophil elastase function.
Am J Respir Cell Mol Biol 1989 Nov
PMID:Comparison of smoker and nonsmoker lavage fluid for the rate of association with neutrophil elastase. 263 56

Alpha-1-antitrypsin (alpha 1AT), a highly pleomorphic 52 kD glycoprotein, functions chiefly as the major inhibitor of neutrophil elastase. Of the known alpha 1AT variants, greater than 95% in the U.S. Caucasian population are those of the "normal" M family, including M1(Ala213), M1(Val213), M2 and M3, with M3 the least common of the group. Quantification of the functional capacity of the M3 protein as an inhibitor of neutrophil elastase demonstrated a Kassociation for neutrophil elastase of 10.1 +/- 1.5 x 10(6) M-1 s-1, a value comparable to the common normal M1(Val213) alpha 1AT. To define the nucleotide sequence of the M3 gene, the five coding exons of the alpha 1AT gene of an M3 homozygote were amplified by the polymerase chain reaction and cloned into the plasmid vector pUC19. Sequence analysis demonstrated that the alpha 1AT M3 gene differs from the alpha 1AT M1(Val213) gene by a single base substitution (Glu376 GAA----Asp376 GAC) and from the alpha 1AT M2 gene by a single base substitution (His101 CAT----Arg101 CGT). To establish the consistency of the alpha 1AT M3 genotype among individuals identified by isoelectric focusing of serum to have the M3 phenotype, analysis of genomic DNA of 16 individuals by means of allele-specific amplification revealed that residues 101 and 376 were Arg and Asp, respectively, in all M3 alleles, while residue 101 was His in all M2 alleles and residue 376 was Glu in all M1 alleles.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1989 Dec
PMID:Characterization of the sequence of the normal alpha-1-antitrypsin M3 allele and function of the M3 protein. 263 59

Alpha-1-antitrypsin (AAT) is the predominant protease inhibitor in human sera. The major physiological role of this inhibitor is to protect elastin fibers in the alveolar structure of the lung from excessive degradation by neutrophil elastase. AAT is synthesized predominantly by hepatocytes, although the AAT gene is expressed to a small degree in the epithelial cells of various tissues. Recent studies have shown that the enhanced liver-specific expression of the AAT gene is controlled by the binding of hepatic nuclear proteins to specific DNA sequences upstream from the structural gene. A variety of mutations within the AAT gene have been identified that result in a partial deficiency or total absence of the inhibitor in sera. Inheritance of a particular combination of these alleles can result in a predisposition towards the development of destructive lung disease. Interestingly, the most common AAT deficiency variant, designated PiZ, causes the mutant protein to accumulate as an insoluble aggregate within the lumen of the hepatic rough endoplasmic reticulum, which is an etiological agent for the development of liver disease. Overall, investigation into the genetic control of AAT has led to an increased understanding of the factors that control hepatic gene expression, as well as mechanisms involved in the pathophysiology of emphysema and liver cirrhosis.
Mol Biol Med 1989 Apr
PMID:Genetic control of human alpha-1-antitrypsin. 269 88

The tight-skin (Tsk) mouse has recently been proposed as a genetic model of emphysema. A morphometric study has shown that emphysema develops quickly, between 15 days and 1 month after birth. Previous biochemical and ultrastructural investigations of the lungs of 1- and 2-month-old Tsk mice revealed the presence of an ongoing elastolytic process. The goal of the present study was to investigate the role of mouse leukocyte elastase (MLE) in the development of emphysema in 1-month-old Tsk mice. Using electron microscopy and an immunogold labeling technique with rabbit anti-MLE IgG, MLE was localized within the lung neutrophils of control and Tsk mice. MLE was also found associated with elastin in the alveolar septa of Tsk but not of control mice. Little or no labeling was associated with other components (collagen, pneumocytes, and endothelium) of alveolar septa of Tsk mice. Lung elastin of control mice, or of control mice rendered emphysematous with porcine pancreatic elastase, showed negligible gold particle density when incubated with gold-conjugated rabbit IgG. Thus, under the present experimental conditions, an aspecific labeling of elastin is unlikely. This study indicates that MLE may be one of the factors responsible for the rapid development of emphysema in Tsk mice.
Exp Mol Pathol 1989 Aug
PMID:Immunoelectron-microscopic demonstration of elastase in emphysematous lungs of tight-skin mice. 276 16

The human protease inhibitor genes alpha 1 antitrypsin (alpha 1-PI) and alpha 1-antichymotrypsin (alpha 1-ACT) are acute-phase proteins which are induced in response to inflammation. These inhibitors function to limit the activity of serine proteases in vivo. alpha 1-PI acts as an inhibitor of neutrophil elastase to protect the elastin fibers of the lung. Genetic deficiencies of alpha 1-PI result in development of chronic pulmonary emphysema. The physiologic role of alpha 1-ACT has not been clearly defined, but it also appears to function in the maintenance of protease-protease inhibitor equilibrium in the lung. Nucleic acid and protein sequence homologies detected between alpha 1-PI and alpha 1-ACT suggested an evolutionary relationship. Gene mapping experiments were performed to determine if these protease inhibitor genes reside at the same chromosomal locus in man. In situ hybridization data demonstrate that both alpha 1-PI and alpha 1-ACT map to the same region, q31-q32.3, on chromosome 14.
Somat Cell Mol Genet 1986 Mar
PMID:Regional location of alpha 1-antichymotrypsin and alpha 1-antitrypsin genes on human chromosome 14. 348 24

Proteolytic activity for [3H]elastin, pyro-Glu-Pro-Val-pNA(S-2484), and Suc-(Ala)3-pNA(AAApNA) was demonstrated in the bound fraction extracted with 2 M KSCN + 0.1% Triton X-100 from hypersensitivity-type murine lepromas in C57BL/6N mice, while elastase-inhibitor activity was separately observed in the soluble fraction extracted with a Tris-saline buffer. Sephacryl S-200 gel chromatography showed a peak of elastolytic activity with approximately 20,000 in molecular weight. The following DEAE-Sepharose chromatography demonstrated three fractions of elastolytic activity (E-I, II, III). The inhibitory profile showed that E-I is a thiol proteinase, while E-II and E-III belong to serine proteinase-type elastases. Both E-II and E-III showed different properties with neutrophil elastase or elastase secreted from cultured macrophages, but identical characteristics to membrane bound-type elastase of monocytes. A lower level of elastolytic activity was detected in the bound fraction of nonhypersensitivity-type murine lepromas in CBA/N mice, suggesting a more involvement of membrane bound-type elastase from monocytes/macrophages during the tissue remodelings of hypersensitivity-type granulomas.
Exp Mol Pathol 1986 Aug
PMID:Elastase activity in granulomatous inflammation in experimental murine leprosy. 353 Aug 2


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