Pulmonary leukosequestration induced by hind limb ischemia

Area of Science:

• Physiology
• Inflammation Research
• Respiratory Medicine

Background:

• Lower torso ischemia is a known cause of acute respiratory failure.
• This failure is linked to the accumulation of inflammatory cells, specifically polymorphonuclear leukocytes (PMNs), in lung tissue.
• The precise mechanisms driving PMN accumulation during ischemia-induced respiratory failure require further elucidation.

Purpose of the Study:

• To investigate the role of ischemia-induced eicosanoid synthesis in driving PMN accumulation in the lungs.
• To determine if inhibiting thromboxane (Tx) synthesis or lipoxygenase activity can mitigate PMN lung infiltration.
• To assess the efficacy of a platelet-activating factor (PAF) receptor antagonist in preventing PMN lung accumulation.

Main Methods:

• Anesthetized rats underwent 4-hour lower torso ischemia induced by bilateral thigh tourniquets.
• Groups were treated with saline vehicle, a thromboxane synthase inhibitor (OKY-046), a lipoxygenase inhibitor (diethylcarbamazine/DEC), or a PAF receptor antagonist (SRI 63-072).
• Plasma TxB2 levels, lung histology, and PMN counts per high power field (HPF) were assessed 4 hours and 1 day post-ischemia.

Main Results:

• Ischemic rats showed significantly elevated plasma TxB2 levels and PMN infiltration in the lungs compared to sham controls.
• OKY-046 treatment markedly reduced TxB2 levels, normalized lung histology, and significantly lowered PMN counts.
• DEC treatment also reduced TxB2 levels and PMN infiltration, while SRI 63-072 had no significant effect on Tx synthesis or PMN sequestration.

Conclusions:

• Ischemia-induced thromboxane (Tx) synthesis plays a significant role in moderating polymorphonuclear leukocyte (PMN) accumulation in the lungs.
• Inhibition of Tx synthesis effectively mitigates ischemia-induced lung PMN infiltration.
• Lipoxygenase inhibition may prevent PMN accumulation by limiting both leukotriene synthesis and Tx production.