Oxidant-induced injury of the pulmonary microvasculature reportedly contributes to an increase in microvascular permeability and
pulmonary hypertension, both of which are principal features of
acute lung injury (ALI). We tested the hypothesis that
antioxidant therapy with
2,3-dihydroxybenzoic acid (DHB), initiated in awake sheep after the development of
sepsis-induced ALI, would ameliorate the progression of these lesions. DHB has many actions that suggested to us the potential for demonstrating benefit in ALI complicating
sepsis; it is a nontoxic
hydroxyl-radical scavenger that also inhibits the
cyclooxygenase pathway and acts as a weak
iron chelator. In preliminary experiments, we demonstrated that pretreatment with DHB prevented an increase in mean pulmonary arterial pressure, plasma
thromboxane A2, measured as its metabolite
thromboxane B2, and lymph total
protein clearance that otherwise followed an infusion of
zymosan-activated plasma (ZAP) in sheep. In subsequent experiments, 12 additional sheep were rendered septic by cecal
ligation and perforation. Twenty-four to 36 h after cecal
ligation and perforation, an increase in lung microvascular permeability was confirmed, because pulmonary lymph flow had increased by 82% while the mean lymph-to-plasma total
protein ratio was unchanged from baseline. At this point, six sheep were then treated with parenteral DHB and six with DHB vehicle for the subsequent 24 h. In contrast to the demonstrated benefit of DHB pretreatment in preventing ALI secondary to an infusion of ZAP, the progressive increase in lymph total
protein clearance that complicated septic
lung injury in the DHB vehicle group throughout this 24-h study period was not ameliorated in the DHB treatment group. However, DHB did prevent a modest increase in mean pulmonary arterial pressures that was demonstrated in the DHB vehicle group throughout this 24-h treatment period. Although pretreatment prevented ALI after a ZAP infusion, we conclude that DHB only incompletely modified
disease progression when administered after the onset of
sepsis-induced ALI because it ameliorated the pulmonary hypertensive response without concurrently modifying an increase in lung microvascular fluid flux.