Effects of Recombinant Human Activated Protein C in Human Models of Endotoxin Administration

Abraham, Edward

doi:10.1513/pats.200501-004ac

Cited by 34 publications

(12 citation statements)

References 50 publications

(43 reference statements)

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“…28 -30 As with the results obtained from the cremaster muscle models of inflammation, 100 U/kg PC also significantly reduced leukocyte recruitment into the lung during LPS-induced ALI in a time-dependent manner that has been shown for APC only. 24,57 Interestingly, in our experimental setting, increasing PC doses to 400 to 800 U/kg did not lead to any further reduction in leukocyte recruitment. Notably, de Kleijn et al 10 used as much as 600 U/kg PC for efficient treatment of patients with meningococcemia.…”

Section: Discussionmentioning

confidence: 53%

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

Frommhold

Tschada

Braach

et al. 2011

The American Journal of Pathology

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Anti-inflammatory properties of protein C (PC) concentrate are poorly studied compared to activated protein C, although PC is suggested to be safer in clinical use. We investigated how PC interferes with the leukocyte recruitment cascade during acute inflammation and its efficacy during murine endotoxemia. We found that similar to activated protein infusion, intravenous PC application reduced leukocyte recruitment in inflamed tissues in a dose-and timedependent manner. During both tumor necrosis factor-␣ induced and trauma-induced inflammation of the cremaster muscle, intravital microscopy revealed that leukocyte adhesion and transmigration, but not rolling, were profoundly inhibited by 100 U/kg PC. Moreover, PC blocked leukocyte emigration into the bronchoalveolar space during lipopolysaccharide (LPS) induced acute lung injury. PC was efficiently activated in a murine endotoxemia model, which reduced leukocyte infiltration of organs and strongly improved survival (75% versus 25% of control mice). Dependent on the inflammatory model, PC provoked a significant inhibition of leukocyte recruitment as early as 1 hour after administration. PC-induced inhibition of leukocyte recruitment during acute inflammation critically involves thrombomodulin-mediated PC activation, subsequent endothelial PC receptor and protease-activated receptor-1-dependent signaling, and down-regulation of intercellular adhesion molecule 1 leading to reduced endothelial inflammatory response. We conclude that during acute inflammation and sepsis, PC is a fast acting and effective therapeutic approach to block leukocyte recruitment and improve survival.

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Section: Discussionmentioning

confidence: 53%

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

Frommhold

Tschada

Braach

et al. 2011

The American Journal of Pathology

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“…APC administration led to a decline in both airspace and tissue neutrophils, indicating that APC may have directly affected neutrophil migration into the lung [20], and/or reduced parenchymal cell death and chemotactic cytokine production.…”

Section: Discussionmentioning

confidence: 99%

Inhaled activated protein C protects mice from ventilator-induced lung injury

et al. 2010

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IntroductionActivated Protein C (APC), an endogenous anticoagulant, improves tissue microperfusion and endothelial cell survival in systemic inflammatory states such as sepsis, but intravenous administration may cause severe bleeding. We have thus addressed the role of APC delivered locally by inhalation in preventing acute lung injury from alveolar overdistention and the subsequent ventilator-induced lung injury (VILI). We also assessed the effects of APC on the activation status of Extracellular- Regulated Kinase 1/2 (ERK) pathway, which has been shown to be involved in regulating pulmonary responses to mechanical stretch.MethodsInhaled APC (12.5 μg drotrecogin-α × 4 doses) or saline was given to tracheotomized C57/Bl6 mice starting 20 min prior to initiation of injurious mechanical ventilation with tidal volume 25 mL/Kg for 4 hours and then hourly thereafter; control groups receiving inhaled saline were ventilated with 8 mL/Kg for 30 min or 4 hr. We measured lung function (respiratory system elastance H), arterial blood gases, surrogates of vascular leak (broncho-alveolar lavage (BAL) total protein and angiotensin-converting enzyme (ACE)-activity), and parameters of inflammation (BAL neutrophils and lung tissue myeloperoxidase (MPO) activity). Morphological alterations induced by mechanical ventilation were examined in hematoxylin-eosin lung tissue sections. The activation status of ERK was probed in lung tissue homogenates by immunoblotting and in paraffin sections by immunohistochemistry. The effect of APC on ERK signaling downstream of the thrombin receptor was tested on A549 human lung epithelial cells by immunoblotting. Statistical analyses were performed using ANOVA with appropriate post-hoc testing.ResultsIn mice subjected to VILI without APC, we observed hypoxemia, increased respiratory system elastance and inflammation, assessed by BAL neutrophil counts and tissue MPO activity. BAL total protein levels and ACE activity were also elevated by VILI, indicating compromise of the alveolo-capillary barrier. In addition to preserving lung function, inhaled APC prevented endothelial barrier disruption and attenuated hypoxemia and the inflammatory response. Mechanistically, we found a strong activation of ERK in lung tissues by VILI, which was prevented by APC, suggestive of pathogenetic involvement of the Mitogen-Activated Kinase pathway. In cultured human lung epithelial cells challenged by thrombin, APC abrogated the activation of ERK and its downstream effector, cytosolic Phospholipase A2.ConclusionsTopical application of APC by inhalation may effectively reduce lung injury induced by mechanical ventilation in mice.

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“…The Infectious Disease Society of America was the only society that found methodological flaws in the guidelines and rejected the guidelines; however, it was not widely publicized. Two further studies, ADDRESS in 2005 [25] and RESOLVE in 2007 [26] warned of issues with rhAPC, but the campaign ignored these studies until the PROWESS-SHOCK study in 2011 [27] when Lily withdrew it from the market. Preventing the creation of conflicted guidelines requires declaration of potential participant conflicts of interest prior to their involvement in guideline development.…”

Section: Overviewmentioning

confidence: 99%

Consensus development for healthcare professionals

Kea

Sun

2014

Intern Emerg Med

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Consensus development sprang from a desire to synthesize clinician and expert opinions on clinical practice and research agendas in the 1950s. And since the American Institute of Medicine formally defined “guidelines” in 1990, there has been a proliferation of clinical practice guidelines (CPG) both formally and informally. This modern decision making tool used by both physicians and patients, requires extensive planning to meet the challenges of consensus development while reaping its rewards. Consensus allows for a group approach with multiple experts sharing ideas to form consensus on topics ranging from appropriateness of procedures to research agenda development. Disagreements can shed light on areas of controversy and launch further discussions. It has five main components: three inputs (defining the task, participant identification and recruitment, and information synthesis), the approach (consensus development by explicit or implicit means), and the output (dissemination of results). Each aspect requires extensive planning a priori as they influence the entire process, from how information will be interpreted, the interaction of participants, the resulting judgment, to whether there will be uptake of results. Implicit approaches utilize qualitative methods and/or a simple voting structure of majority wins, and are used in informal consensus development methods and consensus development conferences. Explicit approaches aggregate results or judgments using explicit rules set a priori with definitions of “agreement” or consensus. Because the implicit process can be more opaque, unforeseen challenges can emerge such as the undue influence of a minority. And yet, the logistics of explicit approaches may be more time consuming and not appropriate when speed is a priority. In determining which method to use, it is important to understand the pros and cons of the different approaches and how it will affect the overall input, approach, and outcome.

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Effects of Recombinant Human Activated Protein C in Human Models of Endotoxin Administration

Cited by 34 publications

References 50 publications

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

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

Inhaled activated protein C protects mice from ventilator-induced lung injury

Consensus development for healthcare professionals

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