Pathophysiology of

5.1. Normal Populations

Bik analysis with dry chemistry strips has facilitated population studies for various groups and ages [15, 17-19]. Screening of presumed healthy school children and adults showed that Bik was associated with inflammation and/ or infection (Table 1). Reference ranges for general and specific populations have been established for daily and hourly excretion rates [4]. In normal children, the interday excretion of Bik is fairly constant (Table 1). Approximately 50% of patients with fever were positive for Bik. Dividing the urine concentration of Bik with the urine creatinine value gives a good estimate of the basal Uri concentration in randomly collected urines [4]. These values agree well with those from a 24-hour urine collection. Immunosuppressed patients with AIDS or those on chemotherapy with suppressed WBC usually do not show increased Bik [4].

5.2. Pregnancy

Bik is normally elevated during pregnancy to prevent premature labor [4]. Clinically, Bik has been administered as a therapeutic agent to prevent premature labor. The expression of Bik decreases in preparation for labor as the quiescent uterine smooth muscle switches to a state of contractility. The mechanism by which Bik prevents premature labor is partly due to an inhibition of smooth muscle Ca2+ influx [83, 84].

5.3. Infection

Inflammation is a common component associated with sepsis, meningitis, as well as respiratory tract, urinary tract, viral, and bacterial infections (Table 1). Bik is elevated during bacterial or viral infection. The presence of urinary Bik correlates well with standard urinalysis tests for urinary tract infections [20]. Endotoxins released from infectious pathogens induce inflammation and immune cell activation. Macrophages release interleukins and cytokines (IL-1, IL-6, IL-12, IL-15, IL-18, TNF-a) on exposure to lipo-polysaccharide (LPS) and lipoteichoic acid (LTA) endotoxins. These cyto-kines act as a chemotactic factors causing immune cell migration to the site of the infection followed by activation and release of proteases. Cytokines also induce increased vascular permeability in the endothelial. Bik suppresses further cytokine release by protease and intern additional migration and activation of immune cells. Additionally, a stabilization of the immune cell membrane prevents further release of proteases [4].


Conditions in Which Urinary Trypsin Inhibitors Are Increased a,b



Acute inflammation


Chronic inflammation


Kidney disease

Acute viral infections Kidney stones Preeclampsia Surgical trauma Transplant rejection Myocardial infarction CHF






Leukemia, all types

Lymphoma, all types

Multiple myeloma

Ovarian cancer



Acute coronary syndrome Crohn's disease Emphysema Hepatitis

Inflammatory bowel disease Rheumatoid arthritis Systemic lupus erythematosus Appendicitis Bacterial meningitis Bacterial sepsis or infections Pneumonia

Upper respiratory tract infection Urinary tract infections Amyloidosis Tubular disease Glomerulonephritis a Increased in bacterial infections such as pneumonia, upper respiratory tract infection, bacterial meningitis, tonsillitis, gastroenteritis, enterocolitis, streptococcal infection, mononucleosis, lymphadenitis, conjunctivitis, and whooping cough.

bIncreased in severe viral infections such as mumps, varicella (chicken pox), influenza A and B, common cold, viral meningitis, infectious mononucleosis, measles (rubeola), or rotavirus-V enteritis. Severe viral infections are defined by increased lymphocyte count.

5.4. Cancer

During invasion and metastasis by malignant cells, proteolytic enzymes are required to disrupt the basement membrane [85-88]. The proteases plasmin and cathepsin are key enzymes used by invading cancer cells. Both proteases are directly inhibited by Bik. Cancer cells use cell-bound plasmin to activate the plasminogen signaling for urokinase. Bik binds to the cell wall and prevents cell-bound plasmin activation. Bik suppresses tumor invasion in the lungs, lymphatics, and ovaries [4]. Affected cells will express Bik and slow invasion by inhibition of cancer cell wall-bound plasmin. Bik is also released from the IaI by plasmin expressed on the surface of cancer cells. Increased levels of Bik have also been found in urine of patients with hematologic malignancies such as multiple myeloma, Hodgkin's and non-Hodgkin's lymphoma, and leukemia [4, 89]. In these cancers, the WBC count is elevated causing increased free elastase in the circulation. Urinary Bik correlates strongly with the presence of Bence-Jones protein in multiple myeloma. Bik can be formed directly by malignant cells or as the result of increased elastase. The former typically predominates since clinical time course shows increased WBC with reduced Bik. However, Bik levels in urine change in parallel with cancer cell number.

5.5. Surgery

Inflammation due to surgery induces Bik in parallel with tissue damage [4, 90]. Bik usually continues to rise during the course of trauma. As an acute-phase indicator, Bik is generated at the site of cellular injury (Table 2). The rapid rate of Bik formation is due to the presence of its proinhibitor form at sites of inflammation. In organ transplantation, urinary Bik levels increase on the day of surgery and peak on or about the third day following surgery when liver function is normal. By the seventh day, urinary Bik levels usually decrease to basal levels. Following surgery, changes in the Bik are more gradual than traditional inflammatory serum markers.

5.6. Kidney Diseases

Glomerulonephritis is the major cause of renal injury leading to failure and is typically associated with infection [4]. In glomerulonephritis, neutrophil polymorphonuclear leukocytes and macrophages cause capillary wall injury mediated by protease release [91]. The proteases elastase and cathespin are known to damage the basement membrane leading to proteinuria due to disrupted network structure and charge barrier [92]. Platelet coagulation and red blood cells (RBC) increase permeability of the basement membrane to proteins [93]. Stabilization of kidney cell membranes occurs on exposure to Bik, causing decreased N-acetyl-d-glucosaminidase (NAG) release due to


Bik Effects on Cellular Response to Inflammation


Biological/pathological events

Events triggered by PAR activation

Endothelial cells

Epithelial cells


Inflammatory cells: mast cells, lymphocytes, neutrophils Neurons Platelets sensory nerve endings smooth muscle and fibroblasts

Chronic proinflammatory response

Mucosal protection

Healing and repair (hemostasis)

Acute proinflammation

Hyperalgesia Clotting

Neurogenic inflammation

Healing and repair (hemostasis)

Leukocyte infiltration (rolling and adhesion), vascular dilation, inflammation mediator release (e.g., histamine, cytokines, eicosanoids) Fluid and electrolyte balance, mucosal secretion, and protection Cell proliferation

Leukocyte infiltration (rolling and adhesion), vascular dilation, inflammation mediator release (e.g., histamine, cytokines, eicosanoids) Formation of neuropeptides Coagulation

Formation of neuropeptides and calcitonin gene and related peptide leading to recruitment of granulocytes Contraction of smooth muscle, proliferation of fibroblasts cell necrosis [38]. Because cell stabilization required the O-linked glycan, this phenomenon was not observed with Bik-lacking glycans [94].

Anti-inflammatory activity of Bik is highly correlated to glomerulonephritis [4, 95,96]. Bik provides protection to renal cells from ischemia/reperfusion injury by reducing immune-mediated apoptotic signals that typically lead to cell death [4, 30, 81]. Bik also has a protective affect on proximal tubule epithelial cells under stress [97]. Bik levels increase with a-1-microglobulin during renal tubule damage [4].

Glomerular lesions, such as those found in diabetes and glomerular nephritis, are characterized by basement membrane thickening and an increase in collagen-like substances within the mesangial regions that ultimately lead to proteinuria. Protease inhibitors prevent thickening of the basement membrane and reduce proteinuria.

5.7. Vascular Disease and Coagulation

Inflammation leads to vasodilation that damages the endothelial and epithelial layers, thus promoting vascular disease [4]. Kallikrein, neutrophil elastase, and mast cell tryptase release kinins from kininogens. Kinins are vascular dilators that regulate blood pressure, affect sodium homeostasis, and alter renal and cardiac function. Increased concentration of kinins leads to increased dilation and decreased blood pressure [98]. Vascular damage and ischemia/reperfusion injury increase with dilation due to neutrophil chemotaxis and adherence to the endothelium and basement membrane.

Bik decreases ischemia/reperfusion injury by inhibiting proteases that cause kinin release [4, 99]. Reversion to a normal blood pressure occurs in two ways: through inhibition of kallikrein with protease inhibitors and by destruction of kinins by kinase. Bik decreases kinin formation through their effect on kallikrein. The duration of kinin formation and destruction ranges from 2 to 30 min [100, 101]. After 30 min, little kinin activity is detectable. As inflammation abates, so does neutrophil chemotaxis and endothelial adherence to the basement membrane. PAR also regulates vascular tone and participates in response to vascular injury. Bik inhibits PAR activation [79, 80].

Multiple factors are involved in the coagulation cascade with Factors VII and X playing critical roles [102]. Factor X cleaves prothrombin into thrombin that in turn activates conversion of fibrinogen into fibrin. Bik has a protective effect against disseminated intravascular coagulation (DIC) during coronary artery bypass grafting surgery (CABG) [4]. Fibrin degradation products, fibrinogen concentrations, prothrombin time, partial thrombo-plastin time, platelet counts, and the number of renal glomeruli with fibrin-thrombin move toward normal values as Bik causes inhibition of coagulation factors, fibrinolysis, and platelet aggregation.

5.8. Diabetes

Chronic inflammation is often associated with diabetes mellitus and autoimmune disorders such as rheumatoid arthritis and organ failure. Hyper-insulinemia increases WBC and elastase [103, 104]. Excess heavy chains can result due to uncoupling of Bik from the cell matrix during chronic inflammation. PAR-triggered cells appear to be a primary cause of gene expression polymorphism and likely precede detectable abnormalities within damaged cells.

The trypsin family of proteases plays a role in acute and chronic pancreatitis, as well as leads to its ultimate destruction [4, 105]. In pancreatitis, active exocrine enzymes are prematurely released inside the pancreatic duct. Various factors can contribute to the development of acute pancreatitis. Trypsinogen, chymotrypsinogen, procarboxypeptidase, and proelastase are inactive proforms of proteolytic enzymes produced by the pancreatic acinar cells. Following secretion these enzymes are activated in a cascade that converts trypsinogen to trypsin in the duodenum and/or small intestine.

Early activation of the enzyme in the pancreas leads to autodigestion, acute hemorrhage, and necrosis [4]. Trypsin in the small bowel converts all pro-forms (including trypsinogen) to their active forms. Bik protects acinar and endocrine pancreatic cells from self-digestion. Factors that prevent premature trypsin release and injury to the pancreas include intracellular localization of zymogens, sustained rise in extracellular calcium, breakdown of F-actin, and activation of the transcription factor NF-kB. Pancreatitis may lead to a hyperstimulation of the immune system resulting in distant organ damage, especially the lungs. In addition, Bik inhibition of enteropeptidase release disrupts the digestive hydrolase cascade [33].

6. Summary uTis are a distinct group of Bik protease inhibitors that are central to the body's innate anti-inflammatory response. Bik provides a measure of acute and chronic inflammatory conditions and allows insight to the cellular response to inflammation. It is therefore plausible that screening for Bik especially in the urine may provide a diagnostic tool for assessing inflammation.


  • 1] Bauer J, Reich Z, III. Antitryptic action of urine. Med Klin 1909; 5:1744-1747.
  • 2] Faarvang HJ. Urinary trypsin inhibitor in man. Scand J Clin Lab Invest 1965; 120:1-83.
  • 3] Fries E, Blom AM. Bikunin—not just a plasma proteinase inhibitor. Int J Biochem Cell Biol 2000; 32:125-137.
  • 4] Pugia MJ, Lott JA. Pathophysiology and diagnostic value of urinary trypsin inhibitors (review). Clin Chem Lab Med 2005; 43:1-16.
  • 5] Kato K. Human urinary trypsin inhibitor: Its structure, biochemical properties and biosynthesis. Igaku Yakugaku 1995; 33:1089-1097.
  • 6] Bost F, Diarra-Mehrpour M, Martin JP. Inter-alpha-trypsin inhibitor proteoglycan family—a group of proteins binding and stabilizing the extracellular matrix. Eur J Biochem 1998; 252:339-346.
  • 7] Fries E, Kaczmarczyk A. Inter-alpha-inhibitor, hyaluronan and inflammation. Acta Biochim Pol 2003; 50:735-742.
  • 8] Salier JP, Rouet P, Raguenez G, Daveau M. The inter-alpha-inhibitor family: From structure to regulation. Biochem J 1996; 315:1-9.
  • 9] Pratt CW, Swaim MW, Pizzo SV. Inflammatory cells degrade inter-alpha-inhibitor to liberate urinary proteinase inhibitors. J Leukoc Biol 1989; 45:1-9.
  • 10] Mizon C, Piva F, Queyrel V, Balduyck M, Hachulla E, Mizon J. Urinary bikunin determination provides insight into proteinase/proteinase inhibitor imbalance in patients with inflammatory diseases. Clin Chem Lab Med 2002; 40:579-586.
  • 11] Thogersen IB, Enghild JJ. Biosynthesis of bikunin proteins in human carcinoma cell line HepG2 and in primary human hepatocytes. J Biol Chem 1995; 270:18700-18709.
  • 12] Vetr H, Gebhard W. Structure of the human alpha-1-microglobulin-bikunin gene. Biol Chem Hoppe Seyler 1990; 371:1185-1196.
  • 13] Zhu Z, Valdes R, Simmons CQ, Linder MW, Pugia MJ, Jortani SA. Analysis of ligand binding by bioaffinity mass spectrometry. Clin Chim Acta 2006; 371(1-2):71-78.
  • 14] Pugia MJ, Jortani SA, Basu M, Sommer R, Kuo HH, Murphy S, et al. Immunological evaluation of urinary trypsin inhibitors in blood urine: Role of N- & O-linked glycoproteins. GlycoconjJ 2006; 24(1):5-15.
  • 15] Pugia MJ, Sommer R, Corey P, Lott JA, Anderson L, Gleason S, et al. The uristatin dipstick is useful in distinguishing upper respiratory from urinary tract infections. Clin Chim Acta 2004; 341:73-81.
  • 16] Brinkmann T, Weilke C, Kleesiek K. Recognition of acceptor proteins by UDP-d-xylose proteoglycan core protein b-d-xylosyltransferase. J Biol Chem 1997; 272:11171-11175.
  • 17] Pugia MJ, Sommer RG, Volkir P, Jortani SA, Valdes R, Lott JA. Serine protease inhibitors as markers of inflammation in atheroscolerosis. Siemens Medical Solution Internal Data Report 2005 (submitted for publication).
  • 18] Pugia MJ, Takemura T, Kuwajima S, Suzuki M, Cast TK, Profit JA, et al. Clinical utility of a rapid test for uristatin. Clin Biochem 2002; 35:105-110.
  • 19] Jortani SA, Pugia MJ, Elin RJ, Thomas M, Womack EP, Cast T, et al. Sensitive noninva-sive marker for diagnosis of probable bacterial or viral infection. J Clin Lab Anal 2004; 18:289-295.
  • 20] Lindstroem KE, Blom A, Johnsson E, Haraldsson B, Fries E. High glomerular permeability of bikunin despite similarity in charge and hydrodynamic size to serum albumin. Kidney Int 1997; 51:1053-1058.
  • 21] Joberg ME, Blom A, Larsson BS, Alston-Smith J, Mats S, Fries E. Plasma clearance of rat bikunin: Evidence for receptor-mediated uptake. Biochem J 1995; 308:881-887.
  • 22] Ohlson M, Sorensson J, Lindstrom K, Blom AM, Fries E, Haraldsson B. Effects of filtration rate on the glomerular barrier and clearance of four differently shaped molecules. Am J Physiol 2001; 281:F103-F113.
  • 23] Kobayashi H, Gotoh J, Hirashima Y, Terao T. Inter-alpha-trypsin inhibitor bound to tumor cells is cleaved into the heavy chains and the light chain on the cell surface. J Biol Chem 1996; 271:11362-11367.
  • 24] Janssen U, Thomas G, Glant T, Phillips A. Expression of inter-alpha-trypsin inhibitor and tumor necrosis factor-stimulated gene 6 in renal proximal tubular epithelial cells. Kidney Int 2001; 60126-60136.
  • 25] Selbi W, de la Motte CA, Hascall VC, Day AJ, Bowen T, Phillips AO. Characterization of hyaluronan cable structure and function in renal proximal tubular epithelial cells. Kidney Int 2006; 70(7):1287-1295.
  • 26] Rose T, Di Cera E. Substrate recognition drives the evolution of serine proteases. J Biol Chem 2002; 277:19243-19246.
  • 27] Perona JJ, Craik CS. Structural basis of substrate specificity in the serine proteases. Protein Sci 1995; 4:337-360.
  • 28] Delaria KA, Muller DK, Marlor CW, Brown JE, Das RC, Roczniak SO, et al. Characterization of placental bikunin, a novel human serine protease inhibitor. J Biol Chem 1997; 272:12209-12214.
  • 29] Kingston BI, Anderson S. Sequences encoding two trypsin inhibitors occur in strikingly similar genomic environments. Biochem J 1986; 233:443-450.
  • 30] Yamasaki F, Tomoaki S, Watanabe M, Mizota M. Uptake of human urinary trypsin inhibitor by the kidney epithelial cell line, LLC-PK1. Pflugers Arch 1996; 433:9-15.
  • 31] Hochstrasser K, Wachter E, Bretzel G. Liberation of Kunitz-type inhibitors from the inter-alpha-trypsin-inhibitor by limited proteolysis. Proc FEBS 1977; 47:225-234.
  • 32] Zhuo L, Salustri A, Kimata K. A physiological function of serum proteoglycan bikunin: The chondroitin sulfate moiety plays a central role. GlycoconjJ 2002; 19:241-247.
  • 33] Hochstrasser K, Schoenberger OL, Rossmanith I, Wachter E. Kunitz-type proteinase inhibitors derived by limited proteolysis of the inter-alpha-trypsin inhibitor. V. Attachments of carbohydrates in the human urinary trypsin inhibitor isolated by affinity chromatography. Hoppe Seylers Z Physiol Chem 1981; 362:1357-1362.
  • 34] Xu Y, Carr PD, Guss JM, Ollis DL. The crystal structure of bikunin from the inter-a-inhibitor complex: A serine protease inhibitor with two kunitz domains. J Mol Biol 1998; 276:955-966.
  • 35] Krowarsch D, Otlewski J. Amino-acid substitutions at the fully exposed P1 site of bovine pancreatic trypsin inhibitor affect its stability. Protein Sci 2001; 10:715-724.
  • 36] Moczydlowski E, Moss GWJ, Lucchesi KJ. Bovine pancreatic trypsin inhibitor as a probe of large conductance Ca2+-activated K+ channels at an internal site of interaction Biochem Pharmacol 1992; 43:21-28.
  • 37] Grzesiak A, Krokoszynska I, Krowarsch D, Buczek O, Dadlez M, Otlewski J. Inhibition of six serine proteinases of the human coagulation system by mutants of bovine pancreatic trypsin inhibitor. J Biol Chem 2000; 275:33346-33352.
  • 38] Kato Y, Kudo M, Shinkawa T, Mochizuki H, Isaji M, Shiromizu I, et al. Role of O-linked carbohydrate of human urinary trypsin inhibitor on its lysosomal membrane-stabilizing property. Biochem Biophys Res Commun 1998; 243:377-383.
  • 39] Kobayashi H, Sugino D, Terao T. Urinary trypsin inhibitor, a Kunitz-type protease inhibitor, modulates tumor necrosis factor-stimulated activation and translocation of protein kinase C in U937 cells. Int J Oncol 1998; 12:95-105.
  • 40] Kobayashi H, Sugino D, She MY, Ohi H, Hirashima Y, Shinohara H, et al. A bifunctional hybrid molecule of the amino-terminal fragment of urokinase and domain II of bikunin efficiently inhibits tumor cell invasion and metastasis. Eur J Biochem 1998; 253:817-826.
  • 41] Hirashima Y, Kobayashi H, Suzuki M, Tanaka Y, Kanayama N, Fujie M, et al. Characterization of binding properties of urinary trypsin inhibitor to cell-associated binding sites on human chondrosarcoma cell line HCS-2/8. J Biol Chem 2001; 276:13650-13656.
  • 42] Kanayama N, Maehara K, Suzuki M, Fujise Y, Terao T. The role of chondroitin sulfate chains of urinary trypsin inhibitor in inhibition of LPS-induced increase of cytosolic free Ca2+ in HL60 cells and HUVEC cells. Biochem Biophys Res Commun 1997; 238:560-564.
  • 43] Milner CM, Day AJ. TSG-6: A multifunctional protein associated with inflammation. J Cell Sci 2003; 116:1863-1873.
  • 44] Mizon C, Mairie C, Balduyck M, Hachulla E, Mizon J. The chondroitin sulfate chain of bikunin-containing proteins in the inter-alpha-inhibitor family increases in size in inflammatory diseases. Eur J Biochem 2001; 268:2717-2724.
  • 45] Mizon J, Capon C, Mizon C, Lemoine J, Rodie-Talbere P. In acute inflammation, the chondroitin-4 sulphate carried by bikunin is not only longer; it is also undersulphated. Biochimie 2003; 85:101-107.
  • 46] Yamada S, Oyama M, Yuki Y, Kato K, Sugahara K. The uniform galactose 4-sulfate structure in the carbohydrate-protein linkage region of human urinary trypsin inhibitor. Eur J Biochem 1995; 233:687-693.
  • 47] Enghild JJ, Thogersen IB, Cheng F, Fransson L, Roepstorff P, Rahbek-Nielsen H. Organization of the inter-a-inhibitor heavy chains on the chondroitin sulfate originating from Ser10 of bikunin: Posttranslational modification of IaI derived bikunin. Biochemistry 1999; 38:11804—11813.
  • 48] Mania-Pramanik J, Potdar SS, Vadigoppula A, Sawant S. Elastase: A predictive marker of inflammation and/or infection. J Clin Lab Anal 2004; 18:153-158.
  • 49] Johnson R, Couser W, Alpers C, Vissers M, Schulze M. The human neutrophils serine proteinases, elastase and cathespin G can mediate glomerular injury in vivo. J Exp Med 1988; 168:1169-1174.
  • 50] Nakatani K, Takeshita S. Vascular endothelial cell injury by activated neutrophil and treatment for the injury. Surg Trauma Immunol Respon 1999; 8:112-114.
  • 51] Wiedow O, Meyer-Hoffert U. Neutrophil serine proteases: Potential key regulators of cell signalling during inflammation. J Intern Med 2005; 257:319-328.
  • 52] Afshar-Kharghan V, Thiagarajan P. Leukocyte adhesion and thrombosis. Curr Opin Hematol 2006; 13:34-39.
  • 53] Trapani JA. Granzymes: A family of lymphocyte granule serine proteases. Genome Biol 2001; 2:30141-30147.
  • 54] Kam CM, Hudig D, Powers JC. Granzymes (lymphocyte serine proteases): Characterization with natural and synthetic substrates and inhibitors. Biochim Biophys Acta 2000; 1477:307-323.
  • 55] Afshar-Kharghan V, Thiagarajan P. Leukocyte adhesion and thrombosis. Curr Opin Hematol 2006; 13:34-39.
  • 56] Wiedow O, Meyer-Hoffert U. Neutrophil serine proteases: Potential key regulators of cell signalling during inflammation. J Intern Med 2005; 257:319-328.
  • 57] Wilharm E, Parry MAA, Friebel R, Tschesche H, Matschineri G, Sommerhoffi CP, et al. Generation of catalytically active granzyme K from Escherichia coli inclusion bodies and identification of efficient granzyme K inhibitors in human plasma. J Biol Chem 1999; 274:27331-27337.
  • 58] Payne V, Kam PCA. Mast cell tryptase: A review of its physiology and clinical significance. Anaesthesia 2004; 59:695-703.
  • 59] Brinkmann T, Schaefers J, Guertler L, Kido H, Niwa Y, Katunuma N, et al. Inhibition of tryptase TL2 from human T4+ lymphocytes and inhibition of HIV-1 replication in H9 cells by recombinant aprotinin and bikunin homologs. J Protein Chem 1997; 16:651-660.
  • 60] Cocks T, Moffatt J. Protease-activated receptors: Sentries for inflammation. Trends Pharmacol Sci 2000; 21:103-108.
  • 61] Nii A, Morishita H, Hirose J, Yamakawa T, Kanamori T. Novel blood coagulation factor inhibitory activities of the second domain of urinary trypsin inhibitor and its variants. Nippon Kessen Shiketsu Gakkaishi 1995; 6:203-207.
  • 62] Nii A, Morishita H, Yamakawa T, Matsusue T, Hirose J, Miura T, et al. Design of variants of the second domain of urinary trypsin inhibitor (R-020) with increased factor Xa inhibitory activity. J Biochem (Tokyo) 1994; 115:1107-1112.
  • 63] Egeblad K, Astrup T. Fibrinolysis and the trypsin inhibitor in human urine. Scand J Clin Lab Invest 1966; 18:181-190.
  • 64] Shinohara H, Kobayashi H, Hirashima Y, Ohi H, Terao T. Urinary trypsin inhibitor (UTI) efficiently inhibits tumor cell invasion and metastasis in the experimental and spontaneous model. J Jpn Soc Cancer Ther 1996; 3:186-195.
  • 65] Campbell DJ. Towards understanding the kallikrein-kinin system: Insights from measurement of kinin peptides. Braz J Med Biol Res 2000; 33:665-677.
  • 66] Campbell DJ. The kallikrein-kinin system in humans. Clin Exp Pharmacol Physiol 2001; 28:1060-1065.
  • 67] Imokawa H. Substances influencing the vascular permeability of an ear burn model in mice. The effectiveness of antihistamines. Sei Marianna Ika Daigaku Zasshi 1991; 19:310-317.
  • 68] Imokawa H, Ando K, Kubota T, Isono E, Inoue H, Ishida H. Study on the kinetics of bradykinin level in the wound produced by thermal injury in the ear burn model in mice. Nippon Yakurigaku Zasshi 1992; 99:445-450.
  • 69] Takada K, Komori M, Notoya A, Tomizawa Y, Ozaki M. Effect of ulinastatin on microcirculation during excessive hemorrhage using fluid therapy. In Vivo 2003; 17:129-136.
  • 70] Morishita H, Yamakawa T, Matsusue T, Kusuyama T, Sameshima-Aruga R, Hirose J, et al. Novel factor Xa and plasma kallikrein inhibitory activities of the second Kunitz-type inhibitory domain of urinary trypsin inhibitor. Thromb Res 1994; 73:193-204.
  • 71] Kanayama N, Maehara K, She L, Belayet H, Khatun S, Tokunaga N, et al. Urinary trypsin inhibitor suppresses vascular smooth muscle contraction by inhibition of Ca2+ influx. Biochim Biophys Acta 1998; 1381:139-146.
  • 72] Bono F, Lamarche I, Herbert JM. Induction of vascular smooth muscle cell growth by selective activation of the proteinase activated receptor-2 (PAR-2). Biochem Biophys Res Commun 1997; 241:762-764.
  • 73] Olear T, Nouza K. Thrombin and trypsin receptors: The same mechanism of signaling on cellular surfaces. Bratisl Lek Listy 1999; 100:75-79.
  • 74] Cottrell G. Protease activated receptors: The role of cell surface proteolysis in signaling. Essays Biochem 2002; 38:169-183.
  • 75] Miike S, McWilliam A, Kita H. Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2. J Immunol 2001; 167:6615-6622.
  • 76] Shibutani Y, Kunihiro Y. Preventive effects of urinastatin on tissue degradation. Yakuri Chiryo 1986; 14:6057-6072.
  • 77] Coelho AM, Ossovskaya V, Bunnett NW. Proteinase-activated receptor-2: Physiological and pathophysiological roles. Curr Med Chem Cardiovasc Hematol Agents 2003; 1:61-72.
  • 78] Rohatgi T, Sedehizade F, Reymann KG, Reiser G. Protease-activated receptors in neuronal development, neurodegeneration, and neuroprotection: Thrombin as signaling molecule in the brain. Neuroscientist 2004; 10:501-512.
  • 79] Day JRS, Punjabi PP, Randi AM, Haskard DO, Landis RC, Taylor KM. Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery. Circulation 2004; 110:2597-2600.
  • 80] Steinberg SF. The cardiovascular actions of protease-activated receptors. Mol Pharmacol 2005; 67:2-11.
  • 81] Kher A, Meldrum KK, Hile KL, Wang M, Tsai BM, Turrentine MW, et al. Aprotinin improves kidney function and decreases tubular cell apoptosis and proapoptotic signaling after renal ischemia-reperfusion. J Thorac Cardiovasc Surg 2005; 130:662-669.
  • 82] Luo JL, Kamata H, Karin M. IKK/NF-reB signaling: Balancing life and death, a new approach to cancer therapy. J Clin Invest 2005; 115:2625-2632.
  • 83] Kanayama N, el Maradny E, Yamamoto N, Tokunaga N, Maehara K, Terao T. Urinary trypsin inhibitor: A new drug to treat preterm labor: A comparative study with ritodrine. Eur J Obstet Gynecol Reprod Biol 1996; 67(2):133-138.
  • 84] Masuda J, Suzuki K, Satoh A, Kojima-Aikawa K, Nakanishi K, Kuroda K, et al. Matsumoto I. Beta-2-glycoprotein I and urinary trypsin inhibitor levels in the plasma of pregnant and postpartum women. Thromb Res 2006; 117:255-261.
  • 85] Kobayashi H, Suzuki M, Hirashima Y, Terao T. The protease inhibitor bikunin, a novel anti-metastatic agent. Biol Chem 2003; 384:749-754.
  • 86] Suzuki M, Kobayashi H, Tanaka Y, Hirashima Y, Kanayama N, Takei Y, et al. Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cell line by overexpression of bikunin. Int J Cancer 2003; 104:289-302.
  • 87] Hirashima Y, Suzuki M, Kobayashi H. Suppression of cancer invasion and metastasis in human ovarian cancer cells transfected with UTI gene. Surg Trauma Immunol Respon 2001; 10:30-36.
  • 88] Kobayashi H, Sugino D, She MY, Ohi H, Hirashima Y, Shinohara H, et al. A bifunctional hybrid molecule of the amino-terminal fragment of urokinase and domain II of bikunin efficiently inhibits tumor cell invasion and metastasis. Eur J Biochem 1998; 253:817-826.
  • 89] Takubo T, Kumura T, Nakamae H, Aoyama Y, Koh KR, Ohta K, et al. Urinary trypsin inhibitor levels in the urine of patients with haematological malignancies. Haematologia (Budap) 2001; 31:267-272.
  • 90] Endo Y. Antishock action of ulinastatin. Surg Trauma Immunol Respon 2003; 12:29-38.
  • 91] Nakatani K, Takeshita S, Tsujimoto H, Kawamura Y, Sekine I. Inhibitory effect of serine protease inhibitors on neutrophil-mediated endothelial cell injury. J Leukoc Biol 2001; 69:241-247.
  • 92] Cochrane CG, Unanue ER, Dixon FJ. A role of polymorphonuclear leukocyte and complement in nephrotoxic nephritis. J Exp Med 1965; 122:99-116.
  • 93] Yamaguchi Y, Ohshiro H, Nagao Y, Odawara K, Okabe K, Hidaka H, et al. Urinary trypsin inhibitor reduces C-X-C chemokine production in rat liver ischemia/reperfusion. J Surg Res 2000; 94:107-115.
  • 94] Suzuki M, Kobayashi H, Tanaka Y, Hirashima Y, Terao T. Structure and function analysis of urinary trypsin inhibitor (UTI): Identification of binding domains and signaling property of UTI by analysis of truncated proteins. Biochim Biophys Acta 2001; 1547:26-36.
  • 95] Koizumi R, Kanai H, Maezawa A, Kanda T, Nojima Y, Naruse T. Therapeutic effects of ulinastatin on experimental crescentic glomerulonephritis in rats. Nephron 2000; 84:347-353.
  • 96] Wakayama T, Mizushima S, Hirose J, Iseki S. Urinary trypsin inhibitor: Production in the liver and reabsorption in the kidney of the rat. Acta Histochem Cytochem 1996; 29:227-236.
  • 97] Nakakuki M, Yamasaki F, Shinkawa T, Kudo M, Watanabe M, Mizota M. Protective effect of human ulinastatin against gentamicin-induced acute renal failure in rats. Can J Physiol Pharmacol 1996; 74:104-111.
  • 98] Chao J, Stallone J, Liang Y, Chen L, Wang D, Chao L. Kallistatin is a potent new vasodilator. J Clin Invest 1997; 100:11-17.
  • 99] Yoshino M. Contribution of TNF-alpha- and IL-6 in hepatic ischemia reperfusion injury. Toho Igakkai Zasshi 1996; 42:530-543.
  • 100] Takada K, Komori M, Notoya A, Tomizawa Y, Ozaki M. Effect of ulinastatin on microcirculation during excessive hemorrhage using fluid therapy. In Vivo 2003; 17:129-136.
  • 101] Takahashi M, Sawaguchi T, Sawaguchi A, Suzuki T. The cytoprotective effect of protease inhibitor on programmed cell death of endothelial cell. Tokyo Joshi Ika Daigaku Zasshi 2001; 71:669-678.
  • 102] Kaplan A, Silverberg M, Dunn J, Ghebrehiwet B. Interaction of the clotting, kinin forming, complement, and fibrinolytic pathways in inflammation. Ann NY Acad Sci 1982; 389:25-38.
  • 103] Collier A, Patrick AW, Hepburn DA, Bell D, Jackson M, Dawes J, et al. Leucocyte mobilization and release of neutrophil elastase following acute insulin-induced hypogly-caemia in normal humans. Diabet Med 1990; 7:506-509.
  • 104] Collier A, Jackson M, Bell D, Patrick AW, Matthews DM, Young RJ, et al. Neutrophil activation detected by increased neutrophil elastase activity in type 1 (insulin-dependent) diabetes mellitus. Diabetes Res 1989; 10:135-138.
  • 105] Hirano T, Manabe T. Human urinary trypsin inhibitor, urinastatin, prevents pancreatic injuries induced by pancreaticobiliary duct obstruction with caerulein stimulation and systemic hypotension in the rat. Arch Surg 1993; 128:1322-1329.

This page intentionally left blank


Arthritis Relief and Prevention

Arthritis Relief and Prevention

This report may be oh so welcome especially if theres no doctor in the house Take Charge of Your Arthritis Now in less than 5-Minutes the time it takes to make an appointment with your healthcare provider Could you use some help understanding arthritis Maybe a little gentle, bedside manner in your battle for joint pain relief would be great Well, even if you are not sure if arthritis is the issue with you or your friend or loved one.

Get My Free Ebook

Post a comment