Methicillin-resistant Staphylococcus aureus-induced vascular leakage is associated with excessive production of nitric oxide and vascular endothelial growth factor

Background

Methicillin-resistant Staphylococcus aureus (MRSA)-related pneumonia and/or sepsis are a frequent serious menace. The aim of the study was to establish a standardized and reproducible model of MRSA-related ovine septic pneumonia and to compare the pathophysiological responses to those seen in a previously established Pseudomonas aeruginosa-induced ovine sepsis model.

Materials and methods

Twenty-four sheep were operatively prepared for chronic study. After 5 days recovery, tracheostomy was performed under anesthesia and injury was given. Sheep were randomly allocated into four groups: (1) Sham group, no injury (n = 6); (2) Smoke group, exposed to smoke inhalation (n = 6); (3) PS group, exposed to smoke inhalation and instilled with P. aeruginosa (2.5 × 10¹¹ CFU) into the lungs by bronchoscope (n = 6); and (4) MRSA group, exposed to smoke inhalation and instilled with MRSA (2.5 × 10¹¹ CFU) into the lungs by bronchoscope (n = 6). Smoke inhalation injury was induced by inhalation of cotton smoke (48 breaths, <40°C). After the injury, animals were awakened and maintained on mechanical ventilation by 100% O₂ for first 3 hours, and thereafter the O₂ concentration was adjusted according to blood gases. The sheep, including the Sham group, were resuscitated by lactated Ringer's solution with an initial rate of 2 ml/kg/hour that was further adjusted according to hematocrit and filling pressure. The experiment lasted 24 hours.

Results

The mean arterial pressure was severely depleted in the MRSA and PS groups, while it was stable in the Sham and Smoke groups. The fluid net balance was significantly higher in the MRSA group compared with the other groups, including the PS group. Plasma nitrite/nitrate was unchanged in the Sham and Smoke groups compared with baseline values. There was an approximately sevenfold increase in Plasma nitrite/nitrate in the MRSA group versus an approximately 2.5-fold increase in the PS group compared with the Sham group 12 hours post-injury (Table 1). The excessive nitric oxide in the MRSA group was associated with a significant increase in lung tissue vascular endothelial growth factor mRNA and its protein expression.

Table 1 (abstract P34)

Conclusion

The severe vascular leakage syndrome seen in the MRSA group may be due to excessive production of nitric oxide and vascular endothelial growth factor, a potent permeability factor. MRSA is largely responsible for these pathological changes rather than smoke inhalation alone.