The leukokinin system; Its role in fluid accumulation in malignancy and inflammation

Greenbaum, Lowell M.; Prakash, Ajai; Semente, Gloria; Johnston, Martha M.

doi:10.1007/bf01986490

Cited by 19 publications

(7 citation statements)

References 4 publications

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“…(35); oral medication of ulcer patients with pepstatin A at 700 mg/day for 6 weeks did not cause any side effects (36). It was not the purpose of this preliminary study to determine accurately a decrease of released virus particles or the activity of the RT, because these parameters do not necessarily reflect viral infectivity.…”

Section: Discussionmentioning

confidence: 97%

Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A.

Seelmeier

Schmidt²,

Türk³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

301

149

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The protease encoded by the human immunodeficiency virus (H1V) processes the viral gag and gag-pol protein precursor by posttranslational cleavage. In this study we have demonstrated by site-specific mutagenesis (Asp -* Thr) and by pepstatin A inhibition that the recombinant HIV protease is an aspartic-type protease. Furthermore, incubation of HIV-infected H9 cells with pepstatin A inhibited part of the intracellular processing of the HIV gag protein yet had no apparent toxicity on HIV-infected cells during 48 hr of incubation.

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Section: Discussionmentioning

confidence: 97%

Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A.

Seelmeier

Schmidt²,

Türk³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

301

149

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“…Cathepsins of rabbit polymor phonuclear (PMN)1 leukocytes are capable of degrading at acid pH many proteins [14], including basement membrane [15], and can also cleave a kinin-like peptide from a plasma substrate [16][17][18]. Similar enzymatic ac tivity was detected also in macrophages and malignant leukocytes [19], The rate of peptide generation by the acid cathepsins is low. Human PMN leukocytes contain a number of neutral proteases [20].…”

Section: Introductionmentioning

confidence: 77%

Neutral Proteases of Human PMN Leukocytes with Kininogenase Activity

Movat¹,

Habal²,

Macmorine³

1976

Int Arch Allergy Immunol

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A neutral protease with kininogenase activity was isolated from human polymorphonuclear (PMN) leukocytes by cation exchange chromatography and gel filtration. The protease appears heterogeneous by cation exchange chromatography, isoelectric focusing and cationic disc gel electrophoresis, but homogeneous by gel filtration, sucrose density gradient ultracentrifugation, SDS-disc gel electrophoresis and immunoelectrophoresis. By carrying out the electrophoresis of the protease in acrylamide gels of varying concentrations, it was shown that they represent charge isomers. The protease was stable at pH 4–10, but labile to heat, being almost completely inactivated when incubated for 30 min at 70°C. It exhibited proteolytic activity between pH 5 and 9, being maximal at 7.5–8.5. The molecular weight of the PMN protease was estimated to be about 20,000 daltons by gel filtration in aqueous buffer and about 26,000–28,000 daltons by SDS-disc gel electrophoresis and gel filtration in Sepharose 6B in the presence of the dissociating agent guanidine HC1. Its sedimentation coefficient was about 2.7S. Corresponding to the charge heterogeneity, by isoelectric focusing, the kinin-generating and esterolytic activities of the PMN granule lysate focused between pH 6.0 and 11.5, whereas the isolated PMN protease focused between 10.0 and 11.8. With respect to kinin generation, caseinolysis, and alanine esterase activity, the protease was inhibited by DFP and certain chloromethyl ketone inhibitors, as well as the plasma protease inhibitory α₁-antitrypsin, α₂-macroglobulin and antithrombin III. Both bradykinin and a methionyl-lysyl-bradykinin-like peptide were generated from highly purified kininogens by a lysosomal lysate containing the PMN protease. However, this assay was done with a crude enzyme preparation which contains an aminopeptidase capable of converting lysyl-bradykinin or methionyl-lysyl-bradykinin to bradykinin. When injected intradermally, the protease induced hyperemia, hemorrhage, and moderate enhancement of vascular permeability, but the mixture of the protease and kininogen induced a marked enhancement of vascular permeability.

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“…The finding of two kinin-generating systems in human fluids differs from murine systems in which only the leukokin-generating system is found [7].…”

Section: Discussionmentioning

confidence: 95%

“…Incubation of the whole human ascites fluid (fluid and cells) at pH 4.0 generated leukokinins, an event that also occurs with murine ascites fluid [7]. When incubations were carried out in the absence of cells, much less leukokinin was produced.…”

Section: Discussionmentioning

confidence: 97%

“…In pathological conditions, such as inflammation or in neoplastic disease, the protease is probably released from cellular sources (such as neoplastic cells or white cells) into the surrounding medium which contains the substrate, leukokininogen; leukokinin formation results [5,6]. Since leukokinin generating systems have been found in murine and human ascites fluid of neoplastic etiology [7][8][9], we have implicated them as causitive mediators of increased permeability and ascites formation in neoplastic disease [5,6]. Further evidence that leukokinins may mediate ascites fluid formation comes from our observations that pepstatin, which is a potent inhibitor of the leukokinin-forming enzymes, significantly reduces murine ascites fluid accumulation when parenterally administered to ascites tumor-bearing mice [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Leukokinin-H generated from human ascites fluid; its isolation and pharmacology

1979

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Leukokinin-H, a pharmacologically active peptide, has been isolated from human ascites fluid following its generation in vitro at acid pH. The peptide has a molecular weight of approximately 2500. The partial sequence of Leu-AlaTyr-Thr-was obtained from the amino-terminal end. Arginine is the terminal amino acid at the carboxyl end.It was demonstrated that while cell-free ascites fluid generates leukokinin-H, the presence of neoplastic cells enhances the formation about 5 fold. A bradykinin-llke peptide was formed in the fluid following storage at a low temperature of 4~The presence of neoplastic cells, however, did not enhance this peptide formation.Procedures are described for the isolation of leukokinln-H by chromatography. The peptide was clearly differentiated from bradykinin, Lys-bradykinin and MetLys-bradyklnin by treatment of the leukoklnin and other kinins with fluorescamine and separation of the fluorescamlne peptides bygel electrophoresls. The pharmacology of leukokiuln-H isolated" from human ascites fluid is described and compared with bradykinin and leukoklnlns PMN and M. Like the other kinins, it is a potent agent in causing vascular permeability. Likewise it is a vasodepressor substance. Unlike bradykinin it has little spasmogenlc activity on the guinea pig ileum. Its pharmacological properties as well as other evidence cited indicates that it may play an important role as a permeability factor in ascites fluid accumulation of neoplastic etiology.

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The leukokinin system; Its role in fluid accumulation in malignancy and inflammation

Cited by 19 publications

References 4 publications

Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A.

Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A.

Neutral Proteases of Human PMN Leukocytes with Kininogenase Activity

Leukokinin-H generated from human ascites fluid; its isolation and pharmacology

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