Complement C5A Antagonist Treatment Improves the Acute Circulatory and Inflammatory Consequences of Experimental Cardiac Tamponade

Érces, Dániel; Nógrády, Miklós; Nagy, Enikő; Varga, Gabriella; Vass, Andrea; Süveges, Gábor; Imai, Masaki; Okada, Noriko; Okada, Hidechika; Boros, Mihály; Kaszaki, József

doi:10.1097/ccm.0b013e31828a6768

Cited by 11 publications

(11 citation statements)

References 26 publications

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“…Our results indirectly suggest so as the levels of HMGB-1 not only correlated with membranous LN but also with potential mechanisms of HMGB-1 production, i.e. complement deposition (14). It would therefore be interesting to determine whether HMGB-1 co-localizes with podocytes or other cell types in renal biopsies from membranous LN patients, although previous studies did not find such correlation (9).…”

Section: Discussionmentioning

confidence: 60%

Urinary high-mobility group box-1 associates specifically with lupus nephritis class V

Jog

Blanco

Putterman

et al. 2016

Lupus

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Introduction High mobility group box 1 protein (HMGB-1) has been implicated in the pathogenesis of lupus nephritis (LN). There is increased HMGB-1 expression in the kidneys and increased levels are observed in serum and urine of patients with LN. This study was performed to determine whether the increased urinary HMGB-1 was specific for active lupus or secondary to renal damage. Methods Urine from 61 lupus patients (32 had active LN and 29 had SLE with no evidence of LN) and 14 control proteinuric patients (all with hypertension and 8 also with diabetes) were included in this study. HMGB-1 was detected by western blot. Urine protein was normalized to urine creatinine to account for volume of the specimen. Results Median normalized urine HMGB-1 levels were significantly elevated in LN patients compared to lupus patients without kidney disease (53.81 vs. 9.46, p<0.001). A difference in median levels was seen between LN classes; with a significant difference between proliferative and membranous disease (33.4 vs. 138.8, p=0.003). Urine protein to urine creatinine ratio (P/C) correlated with urinary HMGB-1 (r=0.52, p<0.001), but across the classes this was true only for membranous disease (r=0.71, p=0.022, proliferative, p=0.63; mixed, p=0.34). Conclusions HMGB-1 is elevated in the urine of patients with active LN. Levels are associated with LN class and higher levels of urinary HMGB-1 are seen in patients with class V when compared to both proliferative and mixed classes. Therefore, urinary HMGB-1 may be suggestive of membranous LN and warrants further evaluation in large lupus cohort and control disease.

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Section: Discussionmentioning

confidence: 60%

Urinary high-mobility group box-1 associates specifically with lupus nephritis class V

Jog

Blanco

Putterman

et al. 2016

Lupus

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“…Moreover, AcPepA is effective against C5a generation in several species, including rodents, swine, and primates, 12,[17][18][19] and decreases the hypersensitivity reaction in human lung tissues in vitro. 20 The wide variety of species in which AcPepA has proved effective suggests its promise as regards the issue of the translation of experimental and clinical results.…”

Section: Discussionmentioning

confidence: 99%

Complement C5a inhibition improves late hemodynamic and inflammatory changes in a rat model of nonocclusive mesenteric ischemia

Érces

Nógrády

Varga

et al. 2016

Surgery

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Background. Nonocclusive mesenteric ischemia (NOMI) can evolve in a variety of low-flow states. Although the mechanisms leading to NOMI-related intestinal necrosis are largely unknown, circumstantial evidence suggests that excessive vasoconstriction and complement activation both play important roles in this process. Because targeting of the circulatory malfunction of the splanchnic area could be of therapeutic relevance, we set out to investigate the long-term effects of treatment with a complement C5a antagonist in a rat model of partial aortic occlusion (PAO)-induced transient mesenteric hypoperfusion. Methods. The mean arterial pressure of the splanchnic area was kept between 30 and 40 mm Hg by 60 minutes of PAO in anesthetized male Sprague-Dawley rats. C5a inhibitor acetyl-peptide-A (AcPepA; 4 mg kg À1 intravenously) or vehicle administration was initiated at the 45th minute of PAO. After 24 hours, the animals were reanesthetized to record the macrohemodynamics and ileal microcirculation, and plasma and tissue samples were taken for determination of high-mobility group box protein-1 (HMGB-1), endothelin-1, tumor necrosis factor (TNF)-a levels, and small intestinal leukocyte infiltration. Epithelial structural changes were visualized by in vivo confocal laser scanning endomicroscopy. Results. At 24 hours after PAO, mean arterial pressure, heart rate, and cardiac output were significantly greater, the intestinal intramural microcirculation was significantly impaired, and plasma HMGB-1, endothelin-1, TNF-a levels, the degree of epithelial damage and leukocyte infiltration was increased. The AcPepA treatment moderated the hemodynamic and microcirculatory changes, and decreased inflammatory activation and histologic signs of mucosal damage. Conclusion. C5a inhibition ameliorated the potentially harmful local mesenteric hypoperfusion and global long-term inflammatory consequences of PAO. This approach is of promise for use in NOMIassociated situations. (Surgery 2016;159:960-71.)

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“…11 Egy további, nagyállatmodel-lünkben igazoltuk, hogy a pericardialis tamponád által kiváltott változások alkalmasak a NOMI akut hemodinamikai és gyulladásos következményeinek részletes vizsgálatára. 12 Jelen tanulmányunk célja a komplement C5a kóroki szerepének és a korai gátlás hatékonyságának vizsgálata volt, a NOMI általunk már validált állatkísérletes modelljeinek alkalmazásával, különös fi gyelemmel a rövid és hoszszú távú hemodinamikai és gyulladásos következményekre.…”

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Komplement C5a-antagonista-terápia hatása nem okklúzív mesenterialis ischaemia állatmodelljeiben

Nógrády

Varga

Szücs

et al. 2017

MaSeb

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Bevezetés: A nem okkluzív mesenterialis ischaemia (NOMI) anatómiai okok nélkül alakul ki, korai diagnosztizálása nehéz, terápiája sem megoldott. Modellkísérleteinkben a komplement C5a gátlásán keresztül a komplementaktiváció szerepét vizsgáltuk a kórfolyamatban. Anyagok és módszerek: A NOMI rövid és hosszú távú hemodinamikai és gyulladásos következményeinek jellemzéséhez Sprague-Dawley patkányokban (n = 28) 60 perces parciális aortaokklúziót (PAO; hasi aorta, truncus coeliacustól proximálisan; arteria femoralis középnyomása: 30-40 Hgmm), míg vietnami törpesertésekben (n = 19) 60 perces pericardialis tamponádot (artériás középnyomás: 40-50 Hgmm) hoztunk létre. A PAO, valamint a tamponád 45. percében komplement C5a-gátló kezelést alkalmaztunk (acetil-peptid-A; 4 mg/kg iv.). Az állatokban monitoroztuk a makro-és mikrokeringést, mértük a leukocytainfi ltrációt, a gyulladásos mediátorok ( endothelin, HMGB-1) plazmaszintjét. Eredmények: Patkányokban a PAO megszüntetése után 24 órával a C5a gátlása csökkentette a szisztémás gyulladásos válasz részeként megemelkedett perctérfogatot (203,1 ± 5 vs. 269,6 ± 8,1 ml/ min/ kg) és arteria mesenterica superior (AMS) áramlását, fokozta az ileum mucosa mikrokeringését (833,5 ± 33,8 vs. 441,9 ± 22,4 μm/s). Az acetilpeptid-A sertésekben átmenetileg növelte az AMS áramlását és tartósan az ileummucosa-kapillárisáramlást (648,1 ± 45,4 vs. 329,8 ± 12,6 μm/s). A kezelt állatoknál alacsonyabb gyulladásos mediátorszintet és szöveti leuko cytainfi ltrációt mértünk mindkét NOMI-modellben. Következtetések: A komplement aktiváció jelentős szerepet játszik a NOMI alatt bekövetkező makro-és mikrokeringési zavar kialakulásában, a C5a gátlása a gyulladásos folyamat mérséklése mellett befolyásolja a NOMI hemodinamikai következményeit is.Kulcsszavak: vékonybél, komplement C5a, mikrokeringés, endothelin, high mobility group box protein-1 Introduction: Non-occlusive mesenteric ischemia (NOMI) develops without anatomical causes. Early diagnosis is challenging and treatments are of questionable effectiveness. We investigated the role of complement activation in the pathophysiology of NOMI in animal models through the inhibition of complement C5a. Materials and methods: 60-min partial aortic occlusion (PAO; abdominal aorta, proximal to celiac trunk; mean arterial pressure: 30-40 mmHg) was established in Sprague-Dawley rats (n = 28) and 60-min cardiac tamponade in minipigs (n = 19; mean arterial pressure: 40-50 mmHg) to observe short-and long-term circulatory and infl ammatory consequences of NOMI. Macro-and microhemodynamics, leukocyte infi ltration, plasma levels of infl ammatory mediators (endothelin, HMGB-1) were measured. C5a inhibitor (Acetyl-Peptid-A; 4 mg/kg iv) was administered at the 45th min of PAO or tamponade, respectively. Results: Twenty-four hours after PAO systemic infl ammatory response increased cardiac output and superior mesenteric artery fl ow (SMAF). C5a inhibition reduced the elevated cardiac output (203.1 ± 5 vs 269.6 ± 8.1 ml/min/kg) and SMAF and increased ileal microcirculation...

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Complement C5A Antagonist Treatment Improves the Acute Circulatory and Inflammatory Consequences of Experimental Cardiac Tamponade

Abstract: These results provide evidence that blockade of the C5a effects significantly influences the acute splanchnic macro- and microhemodynamic complications and decreases the potentially harmful inflammatory consequences of experimental cardiogenic shock.

Cited by 11 publications

References 26 publications

Urinary high-mobility group box-1 associates specifically with lupus nephritis class V

Urinary high-mobility group box-1 associates specifically with lupus nephritis class V

Complement C5a inhibition improves late hemodynamic and inflammatory changes in a rat model of nonocclusive mesenteric ischemia

Komplement C5a-antagonista-terápia hatása nem okklúzív mesenterialis ischaemia állatmodelljeiben

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