Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the
acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of
septic shock and ARDS and hypothesized that blocking the
proteases neutrophil elastase (NE) and
matrix metalloproteinases (MMP-2 and MMP-9) with the modified
tetracycline,
COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3),
laparotomy only; superior mesenteric artery occlusion (SMA) + fecal
blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of
COL-3 12 h before injury. Animals emerged from
anesthesia and were monitored and treated with fluids and
antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple
cytokine concentrations were measured. Pigs were reanesthetized and placed on a
ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed
septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids.
Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma
IL-1 and
IL-6 and in BALF
IL-6,
IL-8,
IL-10, NE, and
protein concentration in the SMA + FC group.
COL-3 treatment prevented
septic shock and ARDS and significantly decreased
cytokine levels in plasma and BALF.
COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic
COL-3 prevented the development of ARDS and unexpectedly also prevented
septic shock in a chronic insidious onset animal model of
sepsis-induced ARDS. The mechanism of this protection is unclear, as
COL-3 inhibited numerous inflammatory mediators. Nevertheless,
COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that
COL-3 may be useful in reducing the morbidity associated with
sepsis and
ischemia/reperfusion injury in patients.