The Role of Neutrophils in Severe Sepsis

Alves-Filho, José C.; Freitas, Aguinaldo de; Spiller, Fernando; Souto, Fabrício Oliveira; Cunha, Fernando

doi:10.1097/shk.0b013e3181818466

Cited by 215 publications

(172 citation statements)

References 76 publications

(64 reference statements)

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“…Owing to impaired migration, sequestration of neutrophils also strikes organs not affected by infection (48). The lungs are particularly susceptible, and impaired lung function correlates with the intensity of neutrophil infiltrates (49,50).…”

Section: Discussionmentioning

confidence: 99%

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

Barratt‐Due

Thorgersen

Egge

et al. 2013

The Journal of Immunology

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Complement and the TLR family constitute two important branches of innate immunity. We previously showed attenuating effects on inflammation and thromogenicity by inhibiting the TLR coreceptor CD14 in porcine sepsis. In the present study, we explored the effect of the C5 and leukotriene B4 inhibitor Ornithodoros moubata complement inhibitor (OmCI; also known as coversin) alone and combined with anti-CD14 on the early inflammatory, hemostatic, and hemodynamic responses in porcine Escherichia coli–induced sepsis. Pigs were randomly allocated to negative controls (n = 6), positive controls (n = 8), intervention with OmCI (n = 8), or with OmCI and anti-CD14 (n = 8). OmCI ablated C5 activation and formation of the terminal complement complex and significantly decreased leukotriene B4 levels in septic pigs. Granulocyte tissue factor expression, formation of thrombin–antithrombin complexes (p < 0.001), and formation of TNF-α and IL-6 (p < 0.05) were efficiently inhibited by OmCI alone and abolished or strongly attenuated by the combination of OmCI and anti-CD14 (p < 0.001 for all). Additionally, the combined therapy attenuated the formation of plasminogen activator inhibitor-1 (p < 0.05), IL-1β, and IL-8, increased the formation of IL-10, and abolished the expression of wCD11R3 (CD11b) and the fall in neutrophil cell count (p < 0.001 for all). Finally, OmCI combined with anti-CD14 delayed increases in heart rate by 60 min (p < 0.05) and mean pulmonary artery pressure by 30 min (p < 0.01). Ex vivo studies confirmed the additional effect of combining anti-CD14 with OmCI. In conclusion, upstream inhibition of the key innate immunity molecules, C5 and CD14, is a potential broad-acting treatment regimen in sepsis as it efficiently attenuated inflammation and thrombogenicity and delayed hemodynamic changes.

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Section: Discussionmentioning

confidence: 99%

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

Barratt‐Due

Thorgersen

Egge

et al. 2013

The Journal of Immunology

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“…Bacterial dissemination leading to multiorgan injury contributes to the high mortality rate associated with sepsis (10,11,19). Whereas many patients survive the initial stages of sepsis, many will develop later clinical complications including nosocomial infections that lead to prolonged hospitalization.…”

Section: Discussionmentioning

confidence: 99%

“…In sepsis, such alterations in neutrophil function are a result of disrupted chemokine signaling and expression of adhesion molecules (18)(19)(20)(21). For example, the appearance of detectable levels of the bacterial products lipopolysaccharide (LPS) or lipoteichoic acid in the circulation of severely infected patients is associated with diminished neutrophil chemotaxis, including neutrophil response to interleukin 8 (IL-8), macro phage inflammatory protein 2 (MIP-2), or keratinocyte-derived chemokine (KC).…”

Section: Introductionmentioning

confidence: 99%

Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing

Park

Jiang

Tadié

et al. 2013

Mol Med

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An inability of neutrophils to eliminate invading microorganisms is frequently associated with severe infection and may contribute to the high mortality rates associated with sepsis. In the present studies, we examined whether metformin and other 5′ adenosine monophosphate-activated protein kinase (AMPK) activators affect neutrophil motility, phagocytosis and bacterial killing. We found that activation of AMPK enhanced neutrophil chemotaxis in vitro and in vivo, and also counteracted the inhibition of chemotaxis induced by exposure of neutrophils to lipopolysaccharide (LPS). In contrast, small interfering RNA (siRNA)-mediated knockdown of AMPKα1 or blockade of AMPK activation through treatment of neutrophils with the AMPK inhibitor compound C diminished neutrophil chemotaxis. In addition to their effects on chemotaxis, treatment of neutrophils with metformin or aminoimidazole carboxamide ribonucleotide (AICAR) improved phagocytosis and bacterial killing, including more efficient eradication of bacteria in a mouse model of peritonitis-induced sepsis. Immunocytochemistry showed that, in contrast to LPS, metformin or AICAR induced robust actin polymerization and distinct formation of neutrophil leading edges. Although LPS diminished AMPK phosphorylation, metformin or AICAR was able to partially decrease the effects of LPS/toll-like receptor 4 (TLR4) engagement on downstream signaling events, particularly LPS-induced IκBα degradation. The IκB kinase (IKK) inhibitor PS-1145 diminished IκBα degradation and also prevented LPS-induced inhibition of chemotaxis. These results suggest that AMPK activation with clinically approved agents, such as metformin, may facilitate bacterial eradication in sepsis and other inflammatory conditions associated with inhibition of neutrophil activation and chemotaxis. Online address: https://doi.org/www.molmed.org

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“…N eutrophils are key cells of the innate immune system that participate in a vast majority of inflammation-related diseases, such as coronary artery diseases, rheumatoid arthritis, and sepsis (1)(2)(3). They are programmed to exit the circulation and chemotax toward epicenters of inflammation, guided by gradients of a variety of inflammatory mediators (4).…”

mentioning

confidence: 99%

P2X1 Ion Channels Promote Neutrophil Chemotaxis through Rho Kinase Activation

Lecut

Frederix

Johnson

et al. 2009

The Journal of Immunology

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ATP, released at the leading edge of migrating neutrophils, amplifies chemotactic signals. The aim of our study was to investigate whether neutrophils express ATP-gated P2X1 ion channels and whether these channels could play a role in chemotaxis. Whole-cell patch clamp experiments showed rapidly desensitizing currents in both human and mouse neutrophils stimulated with P2X1 agonists, αβ-methylene ATP (αβMeATP) and βγMeATP. These currents were strongly impaired or absent in neutrophils from P2X1−/− mice. In Boyden chamber assays, αβMeATP provoked chemokinesis and enhanced formylated peptide- and IL-8-induced chemotaxis of human neutrophils. This agonist similarly increased W-peptide-induced chemotaxis of wild-type mouse neutrophils, whereas it had no effect on P2X1−/− neutrophils. In human as in mouse neutrophils, αβMeATP selectively activated the small RhoGTPase RhoA that caused reversible myosin L chain phosphorylation. Moreover, the αβMeATP-elicited neutrophil movements were prevented by the two Rho kinase inhibitors, Y27632 and H1152. In a gradient of W-peptide, P2X1−/− neutrophils migrated with reduced speed and displayed impaired trailing edge retraction. Finally, neutrophil recruitment in mouse peritoneum upon Escherichia coli injection was enhanced in wild-type mice treated with αβMeATP, whereas it was significantly impaired in the P2X1−/− mice. Thus, activation of P2X1 ion channels by ATP promotes neutrophil chemotaxis, a process involving Rho kinase-dependent actomyosin-mediated contraction at the cell rear. These ion channels may therefore play a significant role in host defense and inflammation.

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The Role of Neutrophils in Severe Sepsis

Cited by 215 publications

References 76 publications

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing

P2X1 Ion Channels Promote Neutrophil Chemotaxis through Rho Kinase Activation

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