Biomedical Engineering Reference
In-Depth Information
their frequency in peripheral blood. One possible mechanism to account for the
selective recruitment of leukocyte subtype is the expression of specii c combination
of endothelial adhesion molecules that will preferentially bind certain leukocytes,
an endothelial area code in the inl amed systemic vasculature analogous to an
address in lymphoid tissue (Marky
et al.
1990, Elliot
et al.
1990).
INTRACELLULAR SIGNALLING MECHANISM
OF HR INJURY
Acute and chronic inl ammations are thought to be central to the pathogenesis of
many diseases. h e process of tissue injury is complex and requires intercellular
communication between ini ltrating leukocytes and endothelium. Migration and
activation of leukocytes is initiated by physical injury, infection, HR or a local
immune response, and require a series of intracellular signals. One of the many
signalling pathways used is the mutagen-activated protein kinase (MAPK) pathway.
h e MAPK signalling pathway is one of the four major signalling systems used by
eukaryotic cells to transduce extracellular signals to intracellular response. h ere
is ample evidence of the role that protein kinases play in the signalling pathways
secondary to HR injury. h e protein kinases initiate several interconnected
downstream cascades regulated by phosphorylation and dephosphorylation
reactions. h e signalling transduction pathways ultimately initiate the nuclear
transcription of the inl ammatory and anti-inl ammatory genes that plays a pivot
role in HR injury (Obata 2000, Herlaar 1999).
MAPK SIGNALLING PATHWAY
h ree major MAPK pathways are known at present: extracellular-regulated
protein kinase [ERK (p42/44)], c-JunNH-terminal kinase [JNK (p46/54)] and P38
mitogen-activated kinase. To date more than 12 MAPKs have been cloned. h eir
products form a complex network of signalling routes that upon stimulation lead
to a variety of cellular responses. Activation of MAPK system produces various
responses against a variety of stimuli. For example, the activation of ERK causes
cell proliferation, transformation and cell dif erentiation, while activation of JNK
and p38 system is responsible for apoptosis, stress response and inl ammation.
h e recruitment of neutrophil is mediated via the generation of pro-inl ammatory
cytokines resulting in the production of chemokines by endothelial and ini ltrating
cells. Neutrophil and macrophage stimulation regulates expression of the TNF-α
IL-8 via MAPK p38. h e β
2
integrins, which are normally present in the leukocyte
cell membrane, require MAPK pathway for their upregulation. h e p38 MAPK
signalling cascade regulates TNF-α-induced expression of VCAM-1 in endothelial
cells, but ICAM-1 is not regulated by p38 but is thought to be regulated through
NFκB. h e mechanism involved in the generation of ROS in leukocyte endothelial
cells is the oxidative burst, which also requires p38 MAPK.
