Proteolysis in the Interstitial Space  book cover
1st Edition

Proteolysis in the Interstitial Space

ISBN 9781466572072
Published August 18, 2016 by CRC Press
313 Pages 19 B/W Illustrations

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Book Description

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.

Table of Contents

Composition and Function of the Interstitial Fluid

Definition of Interstitial Fluid


Cell Secretion in Interstitial Space

Connectivity of the Interstitial Fluid and Other Extravascular Fluids

Relationship of Interstitial Fluid to Lymph

Structure of the Interstitium

Heterogeneity in the Interstitium

Methods for Obtaining Interstitial Fluid and Some Diagnostic Applications

Transport of Drugs and Biologicals in Interstitial Fluid

Transport of Drugs in the Interstitial Space.

Transport of Biologicals in the Interstitial Space.

Tumor Interstitial Fluid

Chapter 2 - The Extracellular Matrix, Basement Membrane and Glycocalyx

Matrices which Modulate Interstitial Fluid Composition

The Extracellular Matrix

Basement Membrane


Chapter 3 - The Biochemistry of Hyaluronan in the Interstitial Space


Introduction to Hyaluronan

Physical Characteristics of Hyaluronan

The Effect of Protein on Hyaluronan Conformation

Solvent and Hyaluronan

Hyaluronan in the Interstitial Space

Effect of Hyaluronan on Enzyme Activity

Specific Interaction of Hyaluronan with Receptors (Hyaldherins)



Other Cell Surface Receptors for Hyaluronan

Hyaluronan Binding to Other Hyaldherins

Low Molecular Weight Hyaluronan

Hyaluronan as a Therapeutic

Hyaluronidase and Drug Delivery in the Interstitial Space

Proteolysis in the Interstitium

Proteolytic Enzymes in the Interstitial Space

ADAM Proteases

ADAMTS Proteases

Comment on Proteolytic Enzymes in the Interstitial Space

The Fibrinolytic System in the Interstitial Space

Components of the fibrinolytic system

The Fibrinolytic System in the Interstitial Space

Origin of Components of the Fibrinolytic System Found in the Interstitium

Effect of Hyaluronan on Components of Fibrinolytic System.

Urokinase-Type Plasminogen Activator

Urokinase-Type Plasminogen Activator Receptor (CD87)

Activation of Plasminogen on Bacterial Surfaces

Plasminogen Receptors on Eukaryotic Cells

Plasminogen and Plasmin


Plasminogen Activator Inhibitor 1 (PAI-1; SerpinE1)

Plasminogen Activator Inhibitor- 2 (PAI-2; SerpinB2)

Plasminogen Activator Inhibitor 3 (PAI-3)

α2-Plasmin inhibitor (SerpinF2)

Kallikrein in the Interstitial Space


Plasma Kallikrein

Tissue Kallikrein (KLK1) and Kallikrein-Related Peptidases

Miscellaneous Observations on Kallikreins and Other Kinin-forming Enzymes in the Interstitial Space

Hyaluronan and KLK1


Matrix Metalloproteinases in the Interstitial Space

Matrix Metalloproteinases

Activation of Matrix Metalloproteinases

Membrane-Bound Matrix Metalloproteinases

Matrix Metalloproteinases and Regulatory Proteolysis

Matrix Metalloproteinases as Biopharmaceuticals

Development of Inhibitors of Matrix Metalloproteinases for Therapeutic Use

Substrate Specificity of Matrix Metalloproteinases.

Tissue Inhibitors of Metalloproteinases (TIMPs)

Chelation of Zinc Ions and Inhibition of Matrix Metalloproteinases.

Compartmentalization and Regulation of Matrix Metalloproteinases.

Coagulation Factors in the Interstitial Space

Coagulation factors and their regulation in the interstitial space

Coagulation Factors in Lymph and Interstitial Fluid



Fibrinogen and Hyaluronan

Factor VII, Factor VIIa, and Tissue Factor

Regulation of Tissue Factor in the Interstitial Space and Cryptic Tissue Factor

Activity of Tissue Factor, Factor VII/VIIa, and Tissue Factor/Factor VIIa not Related to Blood Coagulation

Factor VII and VIIa in the Interstitial Space

Tissue Factor/Factor VIIa and Interstitial Pathology

Tissue Factor/Factor VIIa and Tumor Development

Intrinsic Coagulation Pathway in the Interstitium

Factor IX

Factor VIII and von Willebrand Factor


Formation of Thrombin in the Interstitial Space

Factors Influencing the Activity of Thrombin in the Interstitial Space

Effect of Hyaluronan on Thrombin Activity

Substrates for Thrombin in the Interstitial Space

The Role of Thrombin in Interstitial Fibrosis

Protease Inhibitors in the Interstitial Space

Proteolytic Regulation in the Interstitial Space


Latent Antithrombin

Plasminogen Activator Inhibitor-1


Heparin Cofactor II


Tissue Inhibitors of Metalloproteinases (TIMPs)

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