Biomedical Engineering Reference
In-Depth Information
greatly expanded in recent years and has signii cant clinical implications. h is
work highlights general mechanisms of the adhesive interactions involved in the
migration of neutrophils to sites of injury.
INTRODUCTION
Polymorphonuclear leukocyte (neutrophil) migration across the vessel walls of the
endothelium and into the surrounding tissue is not only a characteristic feature
of the inl ammatory response during host defense (site of injury or infection)
but also occurs under pathological conditions critical to both acute and chronic
inl ammatory disease states. It is well recognized that neutrophil migration from the
vasculature occurs as a multi-step process, governed by the sequential activation of
adhesion proteins and their ligands on both neutrophils and the endothelium (Ley
et al.
2007, Zarbock and Ley 2008). Initially, this process begins by the tethering
to and rolling of neutrophils on the vascular epithelium in response to locally
produced pro-inl ammatory mediators (cytokines, chemokines, tumor necrosis
factor (TNF)-α, interleukin (IL)-1, and lipopolysaccharide (LPS)). Additional
stimulation by endothelial bound chemokines results in the rapid activation
of β
1
and β
2
integrins, leading to the arrest of neutrophils on the endothelium
and subsequent transmigration into tissues. However, central to the function of
neutrophils in host defense is their ability to diapedes across the microvasculature
and migrate through the tissue to the site of infection. A critical initial step in
this process is the attachment of the neutrophils to the basolateral surface of the
epithelium. Once the neutrophils have i rmly adhered, they begin to migrate across
the epithelial monolayer by using a paracellular route. It is also during this leg of
the journey that unrestrained activation of neutrophils may result in the release of
cytotoxic compounds that can cause harm to neighboring cells.
h e molecular mechanisms underlying neutrophil transendothelial migration
have been well characterized and are far better understood than the events that
mediate neutrophil transepithelial migration. Nevertheless, what is evident is
that distinct mechanisms govern the migration of neutrophils across endothelial
surfaces as compared to epithelial surfaces. From an anatomical perspective,
such dif erences are perhaps predicted given that transendothelial migration of
neutrophils occurs in the apical-to-basolateral direction, whereas neutrophil
migration across epithelial surfaces proceeds in the basolateral-to-apical direction.
In addition, neutrophil migration across the epithelium (≥ 20 μm in length) is
signii cantly longer than migration across the endothelium (≤ a few micrometers),
suggesting that neutrophils interact very intimately with the epithelium (Parkos
1997). Another important anatomical dif erence is that neutrophil adhesion to the
endothelium, but not the epithelium, is dependent on an environment of shear force
caused by blood l ow. Given such anatomical dif erences, it is not surprising that
dif erent adhesion interactions facilitate neutrophil movement across endothelial
surfaces as compared to epithelial surfaces.
