Inflammation is a process of vital importance in the defence and
elimination of microorganisms as well as in the repair of the damaged
tissue. However, inadequate or excessive inflammation leads to
inflammatory diseases such as rheumatoid arthritis. Neutrophil
polyntorphonuclear granulocytes (PMN) are important participators in
inflammatory reactions. Endothelial cells (EC) are crucial for the
regulation of inflammatory responses by their capacity to modulate their
expression of adhesion molecules as well as activating molecules.
Mechanisms of adhesion of PMN to human umbilical vein endothelial cells
(HUVEC) were studied in vitro with emphasis on effects of leukotrienes,
lipoxins, cytokines and antirheumatic agents.
Lipoxin A4 (LXA4), but not LXB4, induced an increase in HUVEC binding of
PMN. The kinetic of the adhesive response was intermediate to that of
rapid (e.g. LTB4) and slow acting agonists (e.g. IL-1ß). The LXA4
response was partially blocked by the PAF-receptor antagonist WEB-2086,
indicating the involvement of PAF in the activation process. The LXA4
induced adhesive response was resistant to pertussistoxin (PT),
indicating that the activation process was independent of PT-sensitive
G-proteins. Pre-treatment of EC with LXA4 prior to stimulation with LT134
reduced the adhesive responses conferred by LTB4. Thus, LXA4 seems not to
be a pro- or anti-inflammatory agent but an inflammatory modulator.
The peptido-leukotrienes C4 (LTC4) and LTD4 are potent inflammatory
mediators involved in the pathophysiology of e.g. bronchial asthma. LTD4
induced rapid rises of intracellular Ca2+ in HUVEC as well as PMN, LTC4
only in HUVEC. LTC4 and LTD4, in contrast to LTB4, did not affect the
adhesive responses of HUVEC or PMN. The intracellular release of Ca2+ was
blocked by the peptido-leukotriene blocker SKF 104,353, indicating the
presence and involvement of specific receptors on HUVEC as well as on
PMN.
Peroxisome proliferator-activating receptors (PPAR) are nuclear receptors
that regulates transcription of e.g. enzymes involved in lipid metabolism
but also involved in the regulation of inflammatory responses.
PPAR[alpha] is expressed in EC. However, treatment of HUVEC with the
PPAR[alpha] agonist WY 14,643 had no influence on adhesive interactions
between HUVEC and PMN, indicating that the modulating capacity of PPAR is
conferred at other steps than the adhesive interactions.
Gold sodium thiornalat (GSTM) and auranofin (AF) interfered with adhesive
interactions between PMN and HUVEC induced by IL-1ß. Likewise, GSTM
reduced endothelial expression of E-selectin, AF interfered with
expression of E- selectin as well as of ICAM-1. Prednisolone interfered
with adhesive as well as cytotoxic interactions between PMN and HUVEC, by
multiple effects on the PMN as well as on the HUVEC, including a
hampering effect on cytokine induced E-selectin expression.
Thus, adhesive interactions between EC and PMN (as well as other classes
of leukocytes) are of pivotal importance in inflammatory reactions.
Agents interfering with these interactions will offer more potent and
selective treatments of inflammatory disorders