ABSTRACT
The central topic of this chapter is the regulation of polymorphonuclear leukocyte (particularly, neutrophil) activity by circulatory hemodynamics-derived mechanical stresses. Neutrophil activation in the microcirculation plays a critical role in the initiation and control of in”ammation (de™nition: a cascade of biological processes by multiple immune and tissue-speci™c cell types that
8.1 Introduction: Control of Neutrophil Activity ....................................................................... 139 8.2 Basic Concepts: The Granulocytes ....................................................................................... 141
8.2.1 Polymorphonuclear Leukocytes ............................................................................... 141 8.2.2 Neutrophil Activation and Recruitment during Acute In”ammation....................... 142
8.3 Fluid Mechanical Environment of the Neutrophil ............................................................... 144 8.3.1 Fluid Pressure ........................................................................................................... 145 8.3.2 Fluid Shear Stress ..................................................................................................... 146 8.3.3 Distribution of Fluid Mechanical Stresses over the Neutrophil Surface .................. 148
8.4 Leukocyte Responses to Fluid Pressure ............................................................................... 150 8.5 Mechanobiological Control by Fluid Shear Stress ............................................................... 151
8.5.1 Pseudopod Retraction Model of Neutrophil Deactivation by Fluid Shear Stress ......151 8.5.2 Shear Stress: A Biophysical Modulator of Neutrophil Behavior .............................. 154 8.5.3 The Actin Cytoskeleton, Small GTPases, GPCRs, and Shear-Induced
Pseudopod Retraction ............................................................................................... 157 8.5.4 Integrins and Proteolytic Regulation of Shear-Induced Pseudopod Retraction ....... 161 8.5.5 Second Messengers: Nitric Oxide, Cyclic Guanidine Monophosphate, and
Superoxide ................................................................................................................ 163 8.6 Neutrophil Mechanobiology in Cardiovascular Physiology and Disease ............................ 165
8.6.1 Fluid Flow-Dependent Leukocyte Deactivation in the In Vivo Blood Vessel ......... 165 8.6.2 Chronic In”ammatory Phenotype and Its Putative Role in Impaired
Leukocyte Mechanotransduction of Shear Stress .................................................... 166 8.6.3 Neutrophil Mechanotransduction of Fluid Shear Stress and Cardiovascular
Diseases .................................................................................................................... 166 Acknowledgments .......................................................................................................................... 168 References ...................................................................................................................................... 169
promote an adaptive response of host tissues to noxious insult) (Medzhitov, 2008). In this respect, neutrophils play an essential role in the acute-stage defense against pathogens (e.g., microorganisms, foreign bodies, and inorganic materials) as well as in the repair and management of tissue damage due to injury. As a consequence of their capacity to express potent antimicrobial and tissue degradative agents during early in”ammatory processes, cellular mechanisms must exist to ensure tight regulation of the destructive potential of the polymorphonuclear leukocytes that, if unchecked, may lead to damage to host tissues. Thus, turning off neutrophil in”ammatory processes during the resolution stages of wound healing and infection is just as critical as turning on these activities at the time of infection or tissue injury.
