Proteolysis in the Interstitial Space

Salvatore V. Pizzo, Roger L. Lundblad, Monte S. Willis

• Publisher: CRC Press
• Year: 2016
• ISBN:
  9781315356723
• Edition: 1
• Topic: Medicine
• Subtopic: Biochemistry in Medicine

Most clinical laboratory tests utilize interstitial and extravascular such as blood, urine, cerebral spinal fluid (CSF), and saliva. For example, CSF is monitored in the context of cancer for both diagnostic and therapeutic reasons. And yet, our understanding of the makeup of interstitial fluids, their relationships to disease, as well as their commercial importance in therapeutics and diagnostics remains rudimentary. Although sometimes perceived as static, interstitial and extravascular fluids are surprisingly dynamic. More than half of serum albumin is in the extravascular space. These fluids move rapidly between the intravascular and extravascular spaces - one entire plasma volume is exchanged very nine hours. In the first half of the book, the authors cover fundamental concepts of interstitial fluids, including their composition and function. They then further review the mechanisms by which interstitial fluids are regulated, characterizing the importance of hyaluronan – a major constituent of interstitial spaces and an a component of synovial fluid; and, outlining the regulation of proteolysis in the interstitial space. In the second half of the book, the authors focus on the coagulation system. This system has been studied extensively in the context of vascular spaces. But many of its components exist in the interstitial spaces. Chapters are devoted to the fibrinolytic system, kallikrein, matrix metalloproteinases, coagulation factors, and protease inhibitors – all are interstitial. By covering a unique array of topics with broad application to biomedical scientists, this book expands our understanding of the importance of interstitial spaces and the fluids that move through and reside in this extravascular environment.

1	Composition and Function of the Interstitial Fluid

1.1 DEFINITION OF INTERSTITIAL FLUID

Body water is divided between intracellular and extracellular fluid, with the great bulk being intracellular fluid and approximately 30% extracellular fluid. The latter is divided between extravascular and intravascular fluid (blood plasma).¹ Extravascular fluid can be further demarcated into interstitial fluid and specialized fluids found in the cerebrospinal, synovial, and ocular compartments (aqueous humor of the eye). The peritoneal transudate, synovial fluid, and interstitial fluid share some characteristics related to their formation from plasma. There is evidence for connectivity between brain interstitial fluid and cerebrospinal fluid.^2–5 Abbott² presents evidence for brain interstitial flow into the cerebrospinal fluid and the possibility of cerebrospinal fluid flow into the brain. Iliff and coworkers³ showed that cerebrospinal fluid exchange with brain interstitial fluid provides a mechanism for the removal of brain interstitial solutes. This group^3,4 have designated this exchange between brain interstitial fluid and cerebrospinal fluid as the glymphatic system and suggested that an imbalance in this system could be responsible for brain edema. The term glymphatic is defined as a paravascular fluid exchange pathway that enables brain interstitial and cerebrospinal fluid turnover and is facilitated by glial cells.⁴ Stukas and coworkers⁵ have shown that apolipoprotein A-1 passes into the brain via cerebrospinal fluid. These investigators suggest that apolipoprotein A-1 passes from the vascular system into cerebrospinal fluid by specific cellular transport (transcytosis). The exchange between brain interstitial fluid and cerebrospinal fluid would be confined to the brain and associated nervous tissue with little systemic consequence. That said, there is the curious issue of prothrombin expression in the brain⁶ and the importance of PAR-1 receptors in neurobiology.⁷ Some characteristics of several human body fluids are shown in Table 1.1.

The concept of the interstitial space dates at least to the work of William Harvey in the sixteenth century on the circulation of blood.⁸ Although we could not find a direct mention of the interstitium, it follows from the description of the circulation that there is a process for transport from the circulation to tissue and return. Early work by Claude Bernard and others⁹ defined the interstitial space (milieu intérieur) as the space between the cells, and that space is between the circulatory system and the lymphatics. A more recent definition defines the interstitial space as the space outside the blood vessels and lymphatic vessels that consists of interstitial fluid and the extracellular matrix (ECM).¹⁰ A substantial portion of a number of plasma proteins can be found in the interstitial space as the volume of interstitial fluid is two to three times the size of the plasma volume.^11,12 For example, approximately 60% of total body albumin is in the extravascular space.¹³ The use of the term interstitial fluid is not exclusive to biology, which can lead to some confusion. It is derived from the Latin interstitium, meaning a space between,¹⁴ so it has been used considerably to describe spaces in geological studies.^15–17 Interstitial fluid has poroelastic qualities resulting from its composition, including the maintenance of connective tissue function.^18,19 But this space and its fluid content also play a role in disease. The interstitial space is a dynamic environment where an interplay of proteases, polysaccharides, cytokines, and inflammatory cells dictates the pathophysiological responses to tissue injury. In the subsequent chapters, we will consider the various compartments of this fluid, their components, and their regulation.

TABLE 1.1
Protein Content of Various Human Body Fluids and Secretions

Fluid	Protein (mg/mL)^a	Comment	Refs.
Extracellular fluid	N/A	The body fluid can be divided into two major components: the intracellular fluid and the extracellular fluid. Between 60% and 70% of the body fluid is intracellular in nature, while the remainder is extracellular in nature. The extracellular fluid, in turn, consists of two primary components: intravascular fluid (blood plasma; approximately 25%) and extravascular fluid (approximately 75%). The extravascular fluid consists mostly of interstitial fluid with small specialized fluids in various spaces; specialized fluids include cerebrospinal fluid, synovial fluid, and ocular fluid.	1–5
Blood plasma	78.9 ± 0.5^b	A protein-rich fluid defined by being confined within the vascular system and representing one-quarter to one-fifth of the total extracellular fluid. It is in equilibrium with the interstitial fluid, which feeds into the lymphatic system and is returned to the venous system. Other areas of extracellular fluid include the peritoneal fluid, ocular fluid, and cerebrospinal fluid. Plasma is also defined as the protein-rich fluid obtained by the removal of the cellular elements of whole blood collected with an anticoagulant.	6–8
Blood serum	72.9 ± 0.5^b	A protein-rich fluid derived from the clotting of plasma or whole blood. Most frequently collected by the clotting of whole blood collected without the addition of an anticoagulant. The protein concentration of serum is usually less that of corresponding plasma, reflecting the loss of fibrinogen and other plasma proteins. Serum may also contain products secreted by platelets and other cellular elements during the process of coagulation.	6–8
Interstitial fluid^c	50.9^d	The concentration of protein in interstitial fluid is 40–60% of that in plasma. The volume of interstitial fluid is two to three times larger than plasma volume and the concentration of a given protein in the interstitial fluid depends on the excluded interstitial volume for a specific protein and the size of the protein. Albumin is the most common protein in interstitial fluid, with lower concentrations of larger proteins such as IgG.	9–11
Interstitial fluid	29.8	Plasma protein concentration was given at 70.0 mg/mL; the interstitial volume was 8.4 L, with an excluded interstitial volume of 2.1 L.	12
Interstitial fluid	27.2 18.3	Wick fluid.^e Blister technique.^e	13
Interstitial fluid	37^f 24	Perivascular. Peribronchial.	14
Lymph	26–51^e	Lymph is derived from plasma via interstitial fluid. There is tissue variability in lymph flow rate and regional composition. In this study, as with others, albumin was the major protein. This study also referred to other proteins as members of the classical globulin fractions.	15
Lymph	17–25^f	Protein concentration increased to 44 mg/mL in skin lymph but not muscle lymph after thermal injury.	16
Lymph^g	42	The lymph/plasma ratio was 0.71 for total protein, 0.70 for albumin, and 0.25 for immunoglobulin.	17
Lymph^h	25–27	The protein concentration of lymph was slightly less than that of interstitial fluid. The concentration of lactic dehydrogenase was much higher in interstitial fluid than in lymph; the concentration in lymph in turn is much higher than that in plasma.	18
Lymph^i	27	The protein concentration of lymph was slightly less than that obtained for interstitial fluid (25 mg/mL). Albumin is the major protein (18 mg/mL), with smaller quantities of globulin^j (8.2 mg/mL).	19
Peritoneal fluid	25	Peritoneal fluid is usually obtained only the in the case of ascites; it is labeled a transudate if the protein concentration is less than 25 mg/mL and an exudate if the protein concentration is greater than 25 mg/mL.^k A transudate can result from increased hydrostatic pressure, while an exudate can result from decreased capillary permeability.	20–22
Peritoneal fluid	42.2 ± 6	Peritoneal fluid obtained from norma...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication
• Table of Contents
• Preface
• Acknowledgments
• Authors
• Chapter 1 Composition and Function of the Interstitial Fluid
• Chapter 2 The Extracellular Matrix, Basement Membrane, and Glycocalyx
• Chapter 3 The Biochemistry of Hyaluronan in the Interstitial Space
• Chapter 4 Proteolysis in the Interstitium
• Chapter 5 The Fibrinolytic System in the Interstitial Space
• Chapter 6 Kallikrein in the Interstitial Space
• Chapter 7 Matrix Metalloproteinases in the Interstitial Space
• Chapter 8 Coagulation Factors in the Interstitial Space
• Chapter 9 Protease Inhibitors in the Interstitial Space
• Index