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].

TABLE 1

Conditions in Which Urinary Trypsin Inhibitors Are Increased a,b

Conditions

Studied

Acute inflammation

Cancer

Chronic inflammation

Infection

Kidney disease

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

Pancreatitis

Trauma

Breast

Colon

Esophagus

Leukemia, all types

Lymphoma, all types

Multiple myeloma

Ovarian cancer

Pancreas

Stomach

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

TABLE 2

Bik Effects on Cellular Response to Inflammation

Cells

Biological/pathological events

Events triggered by PAR activation

Endothelial cells

Epithelial cells

Fibroblast

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.

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ADVANCES IN CLINICAL CHEMISTRY, VOL. 44

Arthritis Relief and Prevention

Arthritis Relief and Prevention

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