|
Sepsis in Animals
To determine the effect of inducible nitric oxide synthase (iNOS) on pulmonary neutrophil infiltration in acute lung injury, Razavi and coworkers investigated pulmonary microvascular neutrophil sequestration using intravital videomicroscopy as well as pulmonary neutrophil infiltration assessed by myeloperoxidase activity and lavage neutrophil counts in a murine cecal ligation and perforation model. In septic iNOS–/– mice, fewer neutrophils were sequestered in microvessels and the bronchoalveolar spaces compared with iNOS+/+ mice. In positive to negative chimeras in which iNOS expression was limited to marrow-derived inflammatory cells, pulmonary microvascular neutrophil sequestration and lavage neutrophil counts were restored to levels seen in septic iNOS+/+ mice, whereas pulmonary neutrophil trafficking was similar to iNOS–/– mice in negative to positive chimeras. In vitro cytokine-stimulated neutrophil transendothelial migration was significantly greater for iNOS–/– versus iNOS+/+ neutrophils but was independent of endothelial iNOS. The authors concluded that neutrophil iNOS-derived NO is an important autocrine modulator of neutrophil infiltration into the lungs in sepsis.
Lysozyme M is a proteolytic enzyme found in macrophages that hydrolyses the bacterial cell wall and plays an important role in nonimmune host defense against infection. Markart and coworkers used a transgenic mouse model of Klebsiella pneumoniae lung infection, and compared bacterial killing at 24 hours in wild-type mice, deficient mice (M–/M–), and transgenic mice (Mtg) having enhanced expression of lysozyme M. Bacterial killing in Mtg was 9-fold higher than in wild-type mice, and 43-fold higher than in (M–/M–) mice. None of the latter mice survived beyond 72 hours, whereas 25% of wild-type mice and 75% of Mtg mice survived to 120 hours. The study provides further evidence of the importance of lysozyme in nonimmune defenses against bacterial lung infection.
Activation of coagulation by tissue factor is an early event in the pathogenesis of acute lung injury and organ failure that results from sepsis. To determine whether blockade of tissue factor would attenuate these injuries by preventing fibrin deposition and inflammation, Carraway and coworkers
administered heat-killed E. coli intravenously to 12 baboons, followed 12 hours later by an infusion of live E. coli. Six animals received site-inactivated Factor VIIa (a competitive inhibitor of tissue factor) at 2 hours after the live bacteria, and six animals received vehicle. Animals treated by site-inactivated Factor VIIa displayed less severe lung injury, preserved gas exchange, better lung compliance, better histology scores, lower lung wet-to-dry weight ratios, higher urinary output, attenuation of metabolic acidosis, and protection of renal tubular architecture. Treated animals exhibited attenuation of coagulopathy and lower levels of plasma interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-1 than did the control animals. The authors conclude that blockade of coagulation attenuates acute lung and renal injury in established gram-negative sepsis accompanied by antiinfammatory effects.
ß2 microglobulin knockout mice (ß2M-/-) lack CD8+ T and natural killer T cells. Sherwood and coworkers
determined whether such mice have increased mortality when sepsis is induced by cecal ligation and puncture. Although the ß2 microglobulin knockout mice survived for longer than did wild-type mice, all eventually died. When ß2 microglobulin knockout mice were treated with anti-asialoGM1, to deplete natural killer cells, long-term survival exceeded 70%. Compared with wild-type mice, ß2 microglobulin knockout mice treated with anti-asialoGM1 did not exhibit hypothermia or metabolic acidosis after induction of sepsis and they produced less proinflammatory cytokines. Septic ß2 microglobulin knockout mice treated with anti-asialoGM1 experienced an increase in mortality with adoptive transfer of CD8+ T and natural killer cells. CD8 knockout mice treated with anti-asialoGM1, which are deficient in CD8+ T cells and natural killer cells, had a greater than 40% survival rate after inducing sepsis. Treating wild-type mice with antibodies to CD8 and asialoGM1 increased survival. The authors conclude that increased survival of ß2-microglobulin knockout mice after cecal ligation and perforation is largely consequent to depletion of CD8+ T and natural killer cells.
In a sheep model of septic shock secondary to peritonitis, Sun and coworkers
compared the effects of low-dose vasopressin, with or without norepinephrine, on hemodynamics, histology, and survival. Mean arterial pressure was maintained with all treatments. Blood flow in the superior mesenteric artery was lower in sheep treated with vasopressin plus norepinephrine than in sheep treated with vasopressin alone. Compared with sheep treated with Ringer's lactate (control) or norepinephrine alone, sheep treated with vasopressin alone or vasopressin plus norepinephrine experienced less of an increase in blood lactate and ileal PCO2-gap. Sheep treated with vasopressin had a higher urinary output than the other groups. Survival time was 17 hours in the control group, and was higher with norepinephrine alone (20 hours), vasopressin alone (30 hours), and vasopressin plus norepinephrine (30 hours). Tissue injury was less severe in sheep receiving vasopressin alone or vasopressin plus epinephrine. The authors conclude that low-dose vasopressin (alone or in combination with norepinephrine) improves mesenteric blood flow, limits lactic acidosis and tissue injury, and increases survival in sheep with septic shock secondary to peritonitis.
Tumor necrosis factor- plays an important role in innate immunity and also appears to serve as a growth factor for certain bacteria. Lee and coworkers
investigated this phenomenon in mice. In in vitro studies, tumor necrosis factor- increased the proliferation of Escherichia coli, but not Pseudomonas aeruginosa, in a concentration-dependent manner; antibodies directed against tumor necrosis factor- attenuated the effect. In in vivo studies, however, mice deficient in the gene for tumor necrosis factor- (TNF--/-) experienced a higher mortality after inoculation with intranasal bacteria than did wild-type (TNF-+/+) mice. The TNF--/- mice exhibited an impairment in clearance of bacteria, which was associated with decreased systematic clearance of chemokine macrophage inflammatory protein-, reduced neutrophil recruitment, and depressed expression of neutrophil CD11b and CD16/CD32; these findings suggest that the effect of tumor necrosis factor- on growth of E. coli was outweighed by the recruited neutrophils. Counts of E. coli in the lungs of neutropenic wild-type mice were about 100-fold higher than in TNF--/- mice, and yet survival rates were equivalent in the two groups. The authors conclude that tumor necrosis factor- augments growth of E. coli, both in vitro and in vivo, although the in vivo effect is only apparent in neutropenic animals. An editorial commentary by Mizgerd
accompanies this article.
Platelet endothelial cell adhesion molecule-1 is believed to mediate transendothelial migration of leukocytes after CD11/CD18-mediated adhesion. Tasaka and coworkers
studied the role of this adhesion molecule in the migration of neutrophils across pulmonary capillaries and the bronchial microvasculature in mice and rats. Neutrophil emigration was induced by E. coli, a stimulus eliciting CD11/CD18-dependent emigration, or by Streptococcus pneumoniae, a stimulus inducing CD11/CD18-independent emigration. Antibodies that block platelet endothelial cell adhesion molecule-1 partially inhibited glycogen-induced emigration of neutrophils into the peritoneum; the antibodies, however, did not prevent emigration of neutrophils across either the pulmonary capillaries or the bronchial microvasculature in response to either E. coli or S. pneumoniae. The antibody did not increase the number of neutrophils within the bronchial vessels. The authors conclude that CD11/CD18-dependent or CD11/CD18-independent adhesion pathways may individually lead to migration of neutrophils through the pulmonary or bronchial endothelium independently of platelet adhesion cell adhesion molecule-1.
Citations 1-6 of 6 total displayed.
Pulmonary Neutrophil Infiltration in Murine Sepsis: Role of Inducible Nitric Oxide Synthase
- Habib M. Razavi, Le Feng Wang, Sean Weicker, Marta Rohan, Cedrin Law, David G. McCormack, and Sanjay Mehta
Am. J. Respir. Crit. Care Med. 170: 227 -233. First published online as doi:10.1164/rccm.200306-846OC
[Abstract]
[Full text]
Mouse Lysozyme M Is Important in Pulmonary Host Defense against Klebsiella pneumoniae Infection
- Philipp Markart, Thomas R. Korfhagen, Timothy E. Weaver, and Henry T. Akinbi
Am. J. Respir. Crit. Care Med. 169: 454 -458. First published online as doi:10.1164/rccm.200305-669OC
[Abstract]
[Full text]
Low-Dose Vasopressin in the Treatment of Septic Shock in Sheep
- Qinghua Sun, George Dimopoulos, Duc Nam Nguyen, Zizhi Tu, Nathalie Nagy, Anh Dung Hoang, Peter Rogiers, Daniel De Backer, and Jean-Louis Vincent
Am. J. Respir. Crit. Care Med. 168: 481 -486. First published online as doi:10.1164/rccm.200205-447OC
[Abstract]
[Full text]
ß2 Microglobulin Knockout Mice Are Resistant to Lethal Intraabdominal Sepsis
- Edward R. Sherwood, Cheng Y. Lin, Weike Tao, Christopher A. Hartmann, Jay E. Dujon, Andrew J. French, and Tushar K. Varma
Am. J. Respir. Crit. Care Med. 167: 1641 -1649. First published online as doi:10.1164/rccm.200208-950OC
[Abstract]
[Full text]
Blockade of Tissue Factor: Treatment for Organ Injury in Established Sepsis
- Martha Sue Carraway, Karen E. Welty-Wolf, Debra L. Miller, Thomas L. Ortel, Steven Idell, Andrew J. Ghio, Lars C. Petersen, and Claude A. Piantadosi
Am. J. Respir. Crit. Care Med. 167: 1200-1209.
[Abstract]
[Full text]
Platelet Endothelial Cell Adhesion Molecule-1 in Neutrophil Emigration during Acute Bacterial Pneumonia in Mice and Rats
- Sadatomo Tasaka, Lan Qin, Ariko Saijo, Steven M. Albelda, Horace M. DeLisser, and Claire M. Doerschuk
Am. J. Respir. Crit. Care Med. 167: 164-170.
[Abstract]
[Full text]
|
|
