C1-esterase inhibitor infusion increases survival rates for patients with sepsis*

Igonin, A; Protsenko, D.N.; Galstyan, G. M.; Vlasenko, Alexey V.; Khachatryan, Nana N.; Нехаев, И. В.; Shlyapnikov, Sergey; Лазарева, Н. Б.; Herscu, Paul

doi:10.1097/ccm.0b013e318236edb8

Cited by 64 publications

(40 citation statements)

References 8 publications

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“…It is one of the seven currently known Nox isoforms. Complement has been linked to oxidative stress and PMN activation in models of sepsis and inhibition of complement activation resulted in reduced ROS production and attenuation of PMN migration and activation to the site of injury [91,92]. We have demonstrated that Nox2 is an important mediator of renal fibrosis in kidneys undergoing chronic rejection and chronic cyclosporine induced nephrotoxicity [93,94].…”

Section: Reviewmentioning

confidence: 99%

The role of complement in the pathogenesis of renal ischemia-reperfusion injury and fibrosis

Danobeitia

Djamali

Fernández

2014

Fibrogenesis Tissue Repair

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The complement system is a major component of innate immunity and has been commonly identified as a central element in host defense, clearance of immune complexes, and tissue homeostasis. After ischemia-reperfusion injury (IRI), the complement system is activated by endogenous ligands that trigger proteolytic cleavage of complement components via the classical, lectin and/or alternative pathway. The result is the formation of terminal complement components C3a, C5a, and the membrane attack complex (C5b-9 or MAC), all of which play pivotal roles in the amplification of the inflammatory response, chemotaxis, neutrophil/monocyte recruitment and activation, and direct tubular cell injury. However, recent evidence suggests that complement activity transcends innate host defense and there is increasing data suggesting complement as a regulator in processes such as allo-immunity, stem cell differentiation, tissue repair, and progression to fibrosis. In this review, we discuss recent advances addressing the role of complement as a regulator of IRI and renal fibrosis after organ donation for transplantation. We will also briefly discuss currently approved therapies that target complement activity in kidney ischemia-reperfusion and transplantation.

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Section: Reviewmentioning

confidence: 99%

The role of complement in the pathogenesis of renal ischemia-reperfusion injury and fibrosis

Danobeitia

Djamali

Fernández

2014

Fibrogenesis Tissue Repair

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“…C1-esterase inhibitor (C1-INH) is the major negative regulator of the classical and lectin complement pathway [8]. During acute inflammation, a relative C1-INH deficiency may occur [9]. This could result from inactivation due to elastase released from host neutrophils combined with invading pathogens resulting in overwhelming stimuli [10, 11].…”

Section: Introductionmentioning

confidence: 99%

Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia

Beer

Lagrand

Glas

et al. 2016

Cell Biochem Biophys

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Complement activation plays an important role in the pathogenesis of pneumonia. We hypothesized that inhibition of the complement system in the lungs by repeated treatment with nebulized plasma-derived human C1-esterase inhibitor reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation. This was investigated in a rat model of severe Streptococcus pneumoniae pneumonia. Rats were intra–tracheally challenged with S. pneumoniae to induce pneumonia. Nebulized C1-esterase inhibitor or saline (control animals) was repeatedly administered to rats, 30 min before induction of pneumonia and every 6 h thereafter. Rats were sacrificed 20 or 40 h after inoculation with bacteria. Brochoalveolar lavage fluid and lung tissue were obtained for measuring levels of complement activation (C4b/c), lung injury and inflammation. Induction of pneumonia was associated with pulmonary complement activation (C4b/c at 20 h 1.24 % [0.56–2.59] and at 40 h 2.08 % [0.98–5.12], compared to 0.50 % [0.07–0.59] and 0.03 % [0.03–0.03] in the healthy control animals). The functional fraction of C1-INH was detectable in BALF, but no effect was found on pulmonary complement activation (C4b/c at 20 h 0.73 % [0.16–1.93] and at 40 h 2.38 % [0.54–4.19]). Twenty hours after inoculation, nebulized C1-esterase inhibitor treatment reduced total histology score, but this effect was no longer seen at 40 h. Nebulized C1-esterase inhibitor did not affect other markers of lung injury or lung inflammation. In this negative experimental animal study, severe S. pneumoniae pneumonia in rats is associated with pulmonary complement activation. Repeated treatment with nebulized C1-esterase inhibitor, although successfully delivered to the lungs, does not affect pulmonary complement activation, lung inflammation or lung injury.

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“…In fact, deficiencies of several complement factors render the host more susceptible to bacterial infections (10). In other studies, the C1 esterase inhibitor (C1-INH), a complement regulating factor that inactivates the C1 complex, has been utilized as a therapeutic agent for sepsis (11,12). In our previous examination, we focused on the similarity of symptoms between STSS and C1-INH deficiency, and noted that a decrease in C1-INH level caused by S. pyogenes infection is associated with the pathogenesis (13,14).…”

mentioning

confidence: 99%

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

Honda-Ogawa

Sumitomo

Mori

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillStreptococcus pyogenes secretes various virulence factors for evasion from complement-mediated bacteriolysis. However, full understanding of the molecules possessed by this organism that interact with complement C1q, an initiator of the classical complement pathway, remains elusive. In this study, we identified an endopeptidase of S. pyogenes, PepO, as an interacting molecule, and investigated its effects on complement immunity and pathogenesis. Enzyme-linked immunosorbent assay and surface plasmon resonance analysis findings revealed that S. pyogenes recombinant PepO bound to human C1q in a concentration-dependent manner under physiological conditions. Sites of inflammation are known to have decreased pH levels, thus the effects of PepO on bacterial evasion from complement immunity was analyzed in a low pH condition. Notably, under low pH conditions, PepO exhibited a higher affinity for C1q as compared with IgG, and PepO inhibited the binding of IgG to C1q. In addition, pepO deletion rendered S. pyogenes more susceptible to the bacteriocidal activity of human serum. Also, observations of the morphological features of the pepO mutant strain (⌬pepO) showed damaged irregular surfaces as compared with the wild-type strain (WT). WT-infected tissues exhibited greater severity and lower complement activity as compared with those infected by ⌬pepO in a mouse skin infection model. Furthermore, WT infection resulted in a larger accumulation of C1q than that with ⌬pepO. Our results suggest that interaction of S. pyogenes PepO with C1q interferes with the complement pathway, which enables S. pyogenes to evade complement-mediated bacteriolysis under acidic conditions, such as seen in inflammatory sites.The human pathogen Streptococcus pyogenes is a ␤-hemolytic Gram-positive bacterium that causes a wide variety of diseases in various anatomical sites. Superficial infection of S. pyogenes generally leads to local suppurative lesions, such as seen in pharyngitis and impetigo cases. Such mucosal and skin infections are occasionally followed by onset of immune sequelae, including acute rheumatic fever and acute glomerulonephritis. Furthermore, S. pyogenes infection can also cause invasive diseases, such as necrotizing fasciitis, cellulitis, bacteremia, and streptococcal toxic shock syndrome (STSS), 2 with a high mortality rate, which has been a serious problem throughout the world (1-3).Host possesses various immune systems such as the complement system, one of the most important components of innate immunity, that contributes to host defense against pathogens, especially in the early stage of infection (4). Recognition of an invading pathogen is the trigger for complement pathway activation, and then each complement factor is activated in a sequential manner with precise control (5). Together with opsonization, complement-mediated direct killing of pathogens is attributable to formation of the membrane attack complex (MAC), which consists of late complement factors and induces bacteriolysis by pore formati...

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C1-esterase inhibitor infusion increases survival rates for patients with sepsis*

Cited by 64 publications

References 8 publications

The role of complement in the pathogenesis of renal ischemia-reperfusion injury and fibrosis

The role of complement in the pathogenesis of renal ischemia-reperfusion injury and fibrosis

Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

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