Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A study of the uncharacterized serum inhibitors of hyaluronidase, first described half a century ago, was undertaken. Activity was measured against bovine testicular hyaluronidase using a microtiter-based assay and reverse hyaluronan substrate gel zymography. The predominant inhibitory activity was magnesium-dependent and could be eliminated by protease or chondroitinase digestion and by heat treatment. Kinetics of inhibition were similar against hyaluronidases from testis and snake and bee venoms. The inhibitor had no effect on Streptomyces hyaluronidase, indicating that inhibition was not through protection of the hyaluronan substrate. Inhibition levels in serum were increased in mice following carbon tetrachloride or interleukin-1 injection, inducers of the acute-phase response. Reverse zymography identified a predominant band of 120-kDa relative molecular size, with two bands of greater and one of smaller size. The predominant protein was tentatively identified as a member of the inter-alpha-inhibitor family. Inhibition was also observed using either purified inter-alpha-inhibitor or an inter-alpha-inhibitor-related 120-kDa complex. Inter-alpha-inhibitor, found in the hyaluronan-rich cumulus mass surrounding mammalian ova and the coat of fibroblasts and mesothelial cells, may function to stabilize such matrices by protecting against hyaluronidase degradation. Turnover of circulating hyaluronan is extraordinarily rapid, with a half-life of 2-5 min. Prompt increases in levels of serum hyaluronan occur in patients with shock, septicemia, or massive burns, increases that can be attributed, in part, to suppression of degradation by these acute-phase reactants, the inhibitors of hyaluronidase.
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PMID:Evidence that the serum inhibitor of hyaluronidase may be a member of the inter-alpha-inhibitor family. 1090 71

The inhibitors of hyaluronidase present in mammalian sera, first described half a century ago, have remained uncharacterized. Because of increased interest in hyaluronidases and their hyaluronan substrate, a study of these inhibitors was undertaken recently. The predominant serum inhibitor is magnesium-dependent and is eliminated by protease or chondroitinase digestion, and by heat. Kinetics of inhibition are similar against hyaluronidases from testis, snake and bee venom. The inhibitor has no effect on Streptomyces hyaluronidase; indicating inhibition is not through protection of the hyaluronan substrate. Circulating inhibition levels are increased in mice following carbon tetrachloride or interleukin-1 injection, inducers of the acute-phase response. Reverse hyaluronan gel zymography reveals a predominant band of 120 kDa relative molecular size. Additional studies indicate that the inhibitor resembles a member of the Kunitz type inter-alpha-inhibitor family. Inhibition of hyaluronidase activity is observed using purified inter-alpha-inhibitor and is reversed by antibodies specific for inter-alpha-inhibitor. This molecule, found in the hyaluronan-rich cumulus mass surrounding mammalian ova and the pericellular coat of fibroblasts and mesothelial cells, may function to stabilize such matrices by protecting against hyaluronidase degradation. Turnover of circulating hyaluronan is extraordinarily rapid, with a half-life of two to five min. Prompt increases in levels of serum hyaluronan occur in patients with shock, septicemia or massive burns, increases that may be partly attributed to suppression by these acute phase reactants of the constant and rapid rates of hyaluronan degradation by hyaluronidase. A literature survey of other hyaluronidase inhibitors is also presented.
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PMID:Inhibitors of the hyaluronidases. 1182 90

Granzyme K (GrK) is a member of a highly conserved group of potent serine proteases specifically found in the secretory granules of cytotoxic T lymphocytes and natural killer cells. Based on the report indicating that inter-alpha inhibitor proteins are the physiological inhibitors of GrK and on previous findings that showed a significant decrease in plasma inter-alpha inhibitor proteins in patients with sepsis, it was our aim to determine whether increased levels of uninhibited GrK would contribute to the development of sepsis. To test this hypothesis, a competitive enzyme-linked immunosorbent assay system was developed; and the levels of GrK were measured in plasma samples obtained from healthy controls and 2 sets of patients with sepsis: patients admitted to the emergency department with a putative diagnosis of sepsis and patients with severe sepsis enrolled in a clinical trial. In addition, the molecular form(s) of GrK present in these samples was analyzed by Western blot. The levels of GrK were significantly increased in emergency department patients compared with healthy controls and significantly decreased in patients with severe sepsis enrolled in a clinical trial compared with healthy controls. GrK was detected as high-molecular-weight protein complexes in healthy controls but as complexes of lower molecular weight in the septic patients. The decrease in complex size correlated with the appearance of a band at 26 kDa similar to the size of free GrK. Our results indicate that plasma levels of GrK could serve as a useful diagnostic marker to stage sepsis, permitting better classification of septic patients and enabling targeting of specific treatments, and may play a functional role in the development of sepsis.
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PMID:Altered levels and molecular forms of granzyme k in plasma from septic patients. 1743 53

Inter-alpha-inhibitor, TSG-6, and hyaluronan have important functions in fertility and inflammation. Two subunits of inter-alpha-inhibitor, the heavy chains, form covalent bonds with TSG-6 or hyaluronan in vitro. TSG-6-heavy chain complexes serve as intermediates in the transfer of heavy chains from inter-alpha-inhibitor to hyaluronan. In vivo, in addition to these complexes, stable ternary complexes of hyaluronan with both TSG-6 and heavy chains have been demonstrated in the ovulatory cumulus oophorus. In our ongoing efforts to characterize the multiple interactions between hyaluronan, TSG-6 and inter-alpha-inhibitor, we recently characterized the formation of highly stable complexes of TSG-6 with hyaluronan that had been tethered to a solid surface. Here we show that these hyaluronan-TSG-6 complexes are functionally active and transfer heavy chain subunits from inter-alpha-inhibitor to either free or surface-bound hyaluronan. Transitional hyaluronan-TSG-6-heavy chain complexes do not accumulate in vitro. Our data show the capability for heavy chain transfer by both free TSG-6 and preformed hyaluronan-TSG-6 complexes, suggesting that both might contribute to hyaluronan modification in vivo. Transfer of heavy chains to surface-tethered hyaluronan by either free TSG-6 or surface-tethered hyaluronan-TSG-6 complexes did not affect the CD 44-mediated binding of BW 5147 cells in vitro. We show how TSG-6 and hyaluronan together can deplete inter-alpha-inhibitor and generate bikunin, as has been observed in sepsis, and discuss the role of TSG-6 in the generation of hyaluronan-heavy chain complexes associated with ovulation, arthritis, and sepsis.
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PMID:Transfer of inter-alpha-inhibitor heavy chains to hyaluronan by surface-linked hyaluronan-TSG-6 complexes. 1903 48

Therapy for severe sepsis and septic shock remains a major unmet medical need and novel treatments to regulate the disordered inflammatory response in sepsis are needed if improved outcomes in sepsis are to be realized in the future. Current therapy is primarily supportive and includes timely administration of antibiotics, source control of infection, aggressive fluid resuscitation, organ support and use of activated protein C where clinically indicated. Bacterial mediators including endotoxin and superantigens as well endogenous proinflammatory cytokines are critical to the pathogenesis of sepsis-induced organ failure and are being targeted with numerous molecules and removal devices. Additional therapeutic strategies are focused at restoring the natural anticoagulant levels, blocking deleterious effects of the complement cascade, preserving mitochondrial function, and inhibiting excessive lymphocyte apoptosis. Molecules with pluripotent activity such as inter-alpha inhibitor proteins, sirtuin activators and estrogen-receptor ligands are also being investigated. Efforts are underway to re-establish microbial clearance mechanisms and permit immune reconstitution following sepsis-induced immune suppression. A review of the most current agents being investigated and their current status are presented in this chapter. The organization of this chapter includes sections addressing therapies targeting microbial mediators, including endotoxin, as well as therapies targeting inflammation and coagulation. There is also a section on agents targeting novel mediators and pathways.
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PMID:Future perspectives on regulating pro-and anti-inflammatory responses in sepsis. 2165 51