The
protein C (PC) pathway plays an important role in vascular and immune function, and acquired deficiency during
sepsis is associated with increased mortality in both animal models and in clinical studies. However, the association of acquired PC deficiency with the pathophysiology of
lung injury is unclear. We hypothesized that low PC induced by
sepsis would associate with increased
pulmonary injury and that replacement with activated
protein C (APC) would reverse the activation of pathways associated with injury. Using a cecal
ligation and
puncture (CLP) model of polymicrobial
sepsis, we examined the role of acquired PC deficiency on
acute lung injury assessed by analyzing changes in pulmonary pathology,
chemokine response,
inducible nitric-oxide synthase (iNOS), and the
angiotensin pathway. Acquired PC deficiency was strongly associated with an increase in
lung inflammation and drivers of
pulmonary injury, including
angiotensin (Ang) II,
thymus and activation-regulated chemokine,
plasminogen activator inhibitor (PAI)-1, and iNOS. In contrast, the protective factor
angiotensin-converting enzyme (ACE)-2 was significantly suppressed in animals with acquired PC deficiency. The
endothelial protein C receptor, required for the cytoprotective signaling of APC, was significantly increased post-CLP, suggesting a compensatory up-regulation of the signaling receptor. Treatment of septic animals with APC reduced pulmonary pathology, suppressed the
macrophage inflammatory protein family
chemokine response, iNOS expression, and
PAI-1 activity and up-regulated ACE-2 expression with concomitant reduction in AngII
peptide. These data demonstrate a clear link between acquired PC deficiency and pulmonary inflammatory response in the rat
sepsis model and provide support for the concept of APC as a replacement
therapy in
acute lung injury associated with acquired PC deficiency.