Antithrombin III pretreatment reduces neutrophil recruitment into the lung in a rat model of abdominal sepsis

Overwhelming accumulation of neutrophils is a significant component in septic lung damage, although the signaling mechanisms behind neutrophil infiltration in the lung remain elusive. In the present study, we hypothesized that geranylgeranylation might regulate the inflammatory response in abdominal sepsis. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets. Gene expression of CXC chemokines, tumor necrosis factor-α (TNF-α), and CCL2 chemokine was determined by quantitative RT-PCR in isolated alveolar macrophages. Administration of GGTI-2133 markedly decreased CLP-induced infiltration of neutrophils, edema, and tissue injury in the lung. CLP triggered clear-cut upregulation of Mac-1 on neutrophils. Inhibition of geranylgeranyl transferase reduced CLP-evoked upregulation of Mac-1 on neutrophils in vivo but had no effect on chemokine-induced expression of Mac-1 on isolated neutrophils in vitro. Notably, GGTI-2133 abolished CLP-induced formation of CXC chemokines, TNF-α, and CCL2 in alveolar macrophages in the lung. Geranylgeranyl transferase inhibition had no effect on sepsis-induced platelet shedding of CD40L. In addition, inhibition of geranylgeranyl transferase markedly decreased CXC chemokine-triggered neutrophil chemotaxis in vitro. Taken together, our findings suggest that geranylgeranyl transferase is an important regulator of CXC chemokine production and neutrophil recruitment in the lung. We conclude that inhibition of geranylgeranyl transferase might be a potent way to attenuate acute lung injury in abdominal sepsis.

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Antimicrobial efficacy testing of moxifloxacin during the peritonitis and abscess formation stages of intra-abdominal sepsis: A controlled trial in the rat model

Current Therapeutic Research ◽

10.1016/s0011-393x(02)80086-8 ◽

2002 ◽

Vol 63 (12) ◽

pp. 821-827 ◽

Cited By ~ 4

Author(s):

Ronald L. Cisneros ◽

Andrew B. Onderdonk

Keyword(s):

Rat Model ◽

Controlled Trial ◽

Abdominal Sepsis ◽

Abscess Formation ◽

Antimicrobial Efficacy

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CXCL5-mediated recruitment of neutrophils into the peritoneal cavity ofGdf15-deficient mice protects against abdominal sepsis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1918508117 ◽

2020 ◽

Vol 117 (22) ◽

pp. 12281-12287 ◽

Cited By ~ 3

Author(s):

Isa Santos ◽

Henrique G. Colaço ◽

Ana Neves-Costa ◽

Elsa Seixas ◽

Tiago R. Velho ◽

...

Keyword(s):

Septic Shock ◽

Organ Dysfunction ◽

Peritoneal Cavity ◽

Host Response ◽

Abdominal Sepsis ◽

Neutrophil Recruitment ◽

Life Threatening ◽

Pathogen Control ◽

Circulating Levels ◽

Deficient Mice

Sepsis is a life-threatening organ dysfunction condition caused by a dysregulated host response to an infection. Here we report that the circulating levels of growth and differentiation factor-15 (GDF15) are strongly increased in septic shock patients and correlate with mortality. In mice, we find that peptidoglycan is a potent ligand that signals through the TLR2-Myd88 axis for the secretion of GDF15, and thatGdf15-deficient mice are protected against abdominal sepsis due to increased chemokine CXC ligand 5 (CXCL5)-mediated recruitment of neutrophils into the peritoneum, leading to better local bacterial control. Our results identify GDF15 as a potential target to improve sepsis treatment. Its inhibition should increase neutrophil recruitment to the site of infection and consequently lead to better pathogen control and clearance.

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Relationship between time of reperfusion and E-selectin expression, neutrophil recruitment, and germ cell apoptosis after testicular ischemia in a rat model

Fertility and Sterility ◽

10.1016/j.fertnstert.2007.07.1334 ◽

2008 ◽

Vol 90 (4) ◽

pp. 1517-1522 ◽

Cited By ~ 3

Author(s):

Igor Sukhotnik ◽

Robert Greenblatt ◽

Katya Voskoboinik ◽

Michael Lurie ◽

Arnold G. Coran ◽

...

Keyword(s):

Germ Cell ◽

Rat Model ◽

Cell Apoptosis ◽

Neutrophil Recruitment ◽

Germ Cell Apoptosis ◽

Testicular Ischemia

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Nuclear Factor of Activated T Cells Regulates Neutrophil Recruitment, Systemic Inflammation, and T-Cell Dysfunction in Abdominal Sepsis

Infection and Immunity ◽

10.1128/iai.01569-14 ◽

2014 ◽

Vol 82 (8) ◽

pp. 3275-3288 ◽

Cited By ~ 14

Author(s):

Su Zhang ◽

Lingtao Luo ◽

Yongzhi Wang ◽

Maria F. Gomez ◽

Henrik Thorlacius

Keyword(s):

T Cells ◽

T Cell ◽

Systemic Inflammation ◽

Abdominal Sepsis ◽

Neutrophil Recruitment ◽

Luciferase Reporter ◽

Nuclear Factor ◽

Activated T Cells ◽

Cell Dysfunction ◽

T Cell Dysfunction

ABSTRACTThe signaling mechanisms regulating neutrophil recruitment, systemic inflammation, and T-cell dysfunction in polymicrobial sepsis are not clear. This study explored the potential involvement of the calcium/calcineurin-dependent transcription factor, nuclear factor of activated T cells (NFAT), in abdominal sepsis. Cecal ligation and puncture (CLP) triggered NFAT-dependent transcriptional activity in the lung, spleen, liver, and aorta in NFAT-luciferase reporter mice. Treatment with the NFAT inhibitor A-285222 prior to CLP completely prevented sepsis-induced NFAT activation in all these organs. Inhibition of NFAT activity reduced sepsis-induced formation of CXCL1, CXCL2, and CXCL5 chemokines and edema as well as neutrophil infiltration in the lung. Notably, NFAT inhibition efficiently reduced the CLP-evoked increases in HMBG1, interleukin 6 (IL-6), and CXCL5 levels in plasma. Moreover, administration of A-285222 restored sepsis-induced T-cell dysfunction, as evidenced by markedly decreased apoptosis and restored proliferative capacity of CD4 T cells. Along these lines, treatment with A-285222 restored gamma interferon (IFN-γ) and IL-4 levels in the spleen, which were markedly reduced in septic mice. CLP-induced formation of regulatory T cells (CD4+CD25+Foxp3+) in the spleen was also abolished in A-285222-treated animals. All together, these novel findings suggest that NFAT is a powerful regulator of pathological inflammation and T-cell immune dysfunction in abdominal sepsis. Thus, our data suggest that NFAT signaling might be a useful target to protect against respiratory failure and immunosuppression in patients with sepsis.

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The Effect of Thrombin Inhibitors on Tissue Plasminogen Activator Induced Thrombolysis in a Rat Model

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656319 ◽

1992 ◽

Vol 68 (01) ◽

pp. 064-068 ◽

Cited By ~ 40

Author(s):

Petr Klement ◽

Anita Borm ◽

Jack Hirsh ◽

John Maraganore ◽

Gregory Wilson ◽

...

Keyword(s):

Blood Flow ◽

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Rat Model ◽

Antithrombin Iii ◽

Balloon Catheter ◽

Thrombin Inhibitors ◽

Thrombin Inhibitor ◽

Limited Effectiveness ◽

Tissue Plasminogen

SummarySuccessful coronary thrombolysis depends on rapidly restoring blood flow and maintaining patency of the infarct-related artery. Although widely used as an adjunct to lytic therapy, heparin is limited in its ability to produce these effects. Since the limitations of heparin may reflect its inability to inactivate clot-bound thrombin, we developed a rat model of tissue plasminogen activator (t-PA) induced thrombolysis to compare doses of heparin, hirudin, hirulog (a synthetic hirudin-derived peptide), and D-Phe-Pro-ArgCH2Cl (PPACK) that produced a 4-fold prolongation of the baseline activated partial thromboplastin time (APTT) with saline in terms of their ability to accelerate thrombolysis and to prevent reocclusion. A thrombus rich in red cells and fibrin was formed in the distal aorta by applying an external constrictor after denuding the endothelium with a balloon catheter. Thrombolysis was induced with t-PA (1 mg/kg bolus, followed by 1 mg kg–1 h–1 over 30 min) and the rats were then randomized to receive a concomitant 80 min infusion of a thrombin inhibitor or saline. By continuously monitoring blood flow and pre- and post-stenotic blood pressures, the time to clot lysis, and the number of reocclusions were determined. Compared to saline, heparin had no significant effect on these variables. In contrast, hirudin, hirulog, and PPACK significantly (p <0.01) increased the percentage of the time that the vessel remained patent from 63.9 ± 7.7 to 90.7 ± 2.2, 94.0 ± 0.9, and 94.7 ± 1.0%, respectively by significantly (p <0.01) decreasing the number of reocclusions. The superiority of the antithrombin III-independent inhibitors over heparin supports the hypothesis that the limited effectiveness of heparin in this setting reflects its inability to inactivate clot-bound thrombin. Compared to saline, hirulog and PPACK also significantly (p <0.02) accelerated the time to thrombolysis from 10.5 ± 2.3 to 4.4 ± 0.6, and 4.2 ± 0.8 min, respectively, whereas heparin and hirudin did not. The ability of the lower molecular weight inhibitors of thrombin to accelerate lysis may reflect their greater accessibility to clot-bound thrombin. These findings raise the possibility that the antithrombin III-independent inhibitors of thrombin may not be equally effective as adjuncts to thrombolytic therapy with t-PA.

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