Heme oxygenase and soluble guanylate cyclase mediate the neutrophil migration failure to the lung in severe sepsis induced by pneumonia

Background

Sepsis is the main cause of mortality in ICUs. Primary sources of infection influence the risk of severe sepsis development, and pneumonia is a leading source of this disease. Neutrophils play a critical role in the host defense against acute pulmonary infection since neutrophil-depleted mice with pneumonia had delayed pulmonary bacterial clearance and high mortality. The heme oxygenase (HO) and soluble guanylate cyclase (sGC) activities are known to downregulate inflammatory events, such as neutrophil migration. In the present study we evaluated the role of HO and sGC activities on neutrophil migration to the lung during severe sepsis induced by pneumonia.

Methods

C57BL/6 male mice (18 to 22 g) underwent severe sepsis (SS, 4 × 10⁸CFU/mice) and mild sepsis (MS, 1 × 10⁷ CFU/mice) by intratracheal administration of Klebsiella pneumoniae. A SS mice group was pretreated with HO-1-specific inhibitor (ZnPP IX) or a specific inhibitor of sGC (ODQ). Mice were killed 6 hours after bacteria administration and alveolar neutrophil migration and pulmonary parenchyma leukocyte sequestration were evaluated.

Results

Mice subjected to SS presented a failure of the neutrophil migration towards alveoli and an increased leukocyte sequestration into pulmonar parenchyma tissue when compared with mice subjected to MS. The HO-1 or sGC inhibition in SS mice partially restored the neutrophil migration to pulmonary alveoli and reduced the leukocyte sequestration into the pulmonary parenchyma.

Conclusion

These results suggest that HO-1 and sGC activities mediate the neutrophil migration failure to the lung.