Protein C Concentrate Controls Leukocyte Recruitment during Inflammation and Improves Survival during Endotoxemia after Efficient in Vivo Activation

Frommhold, David; Tschada, Julia Anna; Braach, Natascha; Buschmann, Kirsten; Doerner, Axel; Pflaum, Johanna; Stahl, Marie-Sophie; Wang, Hongjie; Koch, Lutz; Sperandio, Markus; Bierhaus, Angelika; Isermann, Berend; Poeschl, Johannes

doi:10.1016/j.ajpath.2011.07.023

Cited by 19 publications

(22 citation statements)

References 62 publications

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“…Consistent with earlier findings [11], PC profoundly blocked leukocyte adhesion in WT mice (Figure 2(a)). Under controlled conditions, leukocyte adhesion of RAGE -deficient mice was significantly impaired compared to WT mice, whereas the number of adherent leukocytes in Icam-1- deficient mice was comparable to those of WT mice (Figure 2(a)).…”

Section: Resultssupporting

confidence: 93%

Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner

Braach

Buschmann

Pflaum

et al. 2014

Mediators of Inflammation

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By binding β 2-integrins both ICAM-1 and the receptor for advanced glycation end products (RAGE) mediate leukocyte recruitment in a stimulus-dependent manner. Using different inflammatory mouse models we investigated how RAGE and ICAM-1 are involved in anti-inflammatory functions of protein C (PC; Ceprotin, 100 U/kg). We found that, depending on the stimulus, RAGE and ICAM-1 are cooperatively involved in PC-induced inhibition of leukocyte recruitment in cremaster models of inflammation. During short-term proinflammatory stimulation (trauma, fMLP, and CXCL1), ICAM-1 is more important for mediation of anti-inflammatory effects of PC, whereas RAGE plays a major role after longer proinflammatory stimulation (TNFα). In contrast to WT and Icam-1−/− mice, PC had no effect on bronchoalveolar neutrophil emigration in RAGE−/− mice during LPS-induced acute lung injury, suggesting that RAGE critically mediates PC effects during acute lung inflammation. In parallel, PC treatment effectively blocked leukocyte recruitment and improved survival of WT mice and Icam-1-deficient mice in LPS-induced endotoxemia, but failed to do so in RAGE-deficient mice. Exploring underlying mechanisms, we found that PC is capable of downregulating intracellular RAGE and extracellular ICAM-1 in endothelial cells. Taken together, our data show that RAGE and ICAM-1 are required for the anti-inflammatory functions of PC.

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Section: Resultssupporting

confidence: 93%

Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner

Braach

Buschmann

Pflaum

et al. 2014

Mediators of Inflammation

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“…Several anti-inflammatory processes are uniquely represented in the LPS exposed obese mouse lung; for example, IL-10 and IL-13 signaling pathways act to suppress pro-inflammatory cytokine production in T-cells, monocytes and macrophages (Lentsch et al ., 1999; Opal and DePalo, 2000; Frommhold et al ., 2011). Taken together, these gene changes suggest a more extensive inflammatory and immune response to endotoxin in obese mice, which includes both pro-inflammatory pathways as well as those regulatory gene products that enable inflammatory resolution as well as prevent the overproduction of ROS.…”

Section: Resultsmentioning

confidence: 99%

Diet-induced obesity reprograms the inflammatory response of the murine lung to inhaled endotoxin

Tilton¹,

Waters²,

Karin³

et al. 2013

Toxicology and Applied Pharmacology

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The co-occurrence of environmental factors is common in complex human diseases and, as such, understanding the molecular responses involved is essential to determine risk and susceptibility to disease. We have investigated the key biological pathways that define susceptibility for pulmonary infection during obesity in diet-induced obese (DIO) and regular weight (RW) C57BL/6 mice exposed to inhaled lipopolysaccharide (LPS). LPS induced a strong inflammatory response in all mice as indicated by elevated cell counts of macrophages and neutrophils and levels of proinflammatory cytokines (MDC, MIP-1γ, IL-12, RANTES) in the bronchoalveolar lavage fluid. Additionally, DIO mice exhibited 50% greater macrophage cell counts, but decreased levels of the cytokines, IL-6, TARC, TNF-α, and VEGF relative to RW mice. Microarray analysis of lung tissue showed over half of the LPS-induced expression in DIO mice consisted of genes unique for obese mice, suggesting that obesity reprograms how the lung responds to subsequent insult. In particular, we found that obese animals exposed to LPS have gene signatures showing increased inflammatory and oxidative stress response and decreased antioxidant capacity compared to RW. Because signaling pathways for these responses can be common to various sources of environmentally induced lung damage, we further identified biomarkers that are indicative of specific toxicant exposure by comparing gene signatures after LPS exposure to those from a parallel study with cigarette smoke. These data show obesity may increase sensitivity to further insult and that co-occurrence of environmental stressors result in complex biosignatures that are not predicted from analysis of individual exposures.

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“…The decreased neutrophils infiltration in the APC-treated group can be attributed to many mechanisms. APC has a significant inhibition of leukocyte recruitment [12]. APC is effective to inhibit the activation of leukocytes [30].…”

Section: Discussionmentioning

confidence: 99%

“…It is known to be critical in regulating microvascular coagulation [9] and its action on microcirculation during endotoxemia has been noted [10]. It also has antiinflammatory properties by blocking tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8, and inhibits neutrophils chemotaxis [11,12]. Therefore, APC manifests multiple effects with antithrombotic, profibrinolytic, and anti-inflammatory activities.…”

Section: Introductionmentioning

confidence: 96%

Activated protein C attenuates ischemia-reperfusion-induced acute lung injury

Cui

Peng

Huang

et al. 2015

Experimental Lung Research

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Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions, such as lung transplantation, acute pulmonary embolism after thrombolytic therapy, re-expansion of collapsed lung from pneumothorax, or pleural effusion, cardiopulmonary bypass, etc. Because mortality remains high despite advanced medical care, prevention and treatment are important clinical issues. Activated protein C (APC) manifests multiple activities with antithrombotic, profibrinolytic, and anti-inflammatory effects. We therefore conducted this study to determine the beneficial effects of APC in IR-induced ALI. IR-induced ALI was conducted in a rat model of isolated-perfused lung in situ. The animals were divided into the control group, IR group, and IR+APC group. There were six adult male Sprague-Dawley rats in each group. The IR caused significant pulmonary microvascular hyperpermeability, pulmonary edema and dysfuction, increased cytokines (tumor necrosis factor (TNF)-α, IL-17, CXCL-1), and neutrophils infiltration in lung tissues. Administration of APC significantly attenuated IR-induced ALI with improving microvascular permeability, pulmonary edema, pulmonary dysfunction, and suppression inflammatory response. The current study demonstrates the beneficial effects of APC in IR-induced ALI. This protective effect is possibly associated with the inhibition of TNF-α, IL-17A, CXCL1, and neutrophils infiltration in lung tissues. However, the current results were obtained in an animal model and it is still necessary to confirm these findings in human subjects. If we can demonstrate the benefits of APC to protect IR lung injury, we can postulate that APC is a potential therapeutic drug for lung preservation.

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Protein C Concentrate Controls Leukocyte Recruitment during Inflammation and Improves Survival during Endotoxemia after Efficient in Vivo Activation

Cited by 19 publications

References 62 publications

Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner

Anti-Inflammatory Functions of Protein C Require RAGE and ICAM-1 in a Stimulus-Dependent Manner

Diet-induced obesity reprograms the inflammatory response of the murine lung to inhaled endotoxin

Activated protein C attenuates ischemia-reperfusion-induced acute lung injury

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