A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model

Ganopolsky, Jorge G.; Castellino, Francis J.

doi:10.1016/s0002-9440(10)63401-3

Cited by 61 publications

(53 citation statements)

References 76 publications

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“…Prolongation and decreased rate of the phase 4 pacemaker potential by LPS are consistent with our previous report that LPS inhibits the "funny current," I f , in HL-1 cells (41) and that it also inhibits HCN channels in native murine sino-atrial node cells and those expressed in HEK293 cells (19). This, as well as an LPS inhibition of I Na and positive shift in threshold voltage, explains, in part, the bradycardia in mice following experimental sepsis by cecal ligation and puncture (7). Prolongation of the action potential duration in HL-1 cells by LPS most likely results from its inhibition of the rapid, delayed rectifier K ϩ current, I Kr .…”

Section: Discussionsupporting

confidence: 91%

Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes

Wondergem

Graves

et al. 2012

American Journal of Physiology-Cell Physiology

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Wondergem R, Graves BM, Li C, Williams DL. Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes. Am J Physiol Cell Physiol 303: C825-C833, 2012. First published August 15, 2012; doi:10.1152/ajpcell.00173.2012.-Sepsis has deleterious effects on cardiac function including reduced contractility. We have shown previously that lipopolysaccharides (LPS) directly affect HL-1 cardiac myocytes by inhibiting Ca 2ϩ regulation and by impairing pacemaker "funny" current, I f. We now explore further cellular mechanisms whereby LPS inhibits excitability in HL-1 cells. LPS (1 g/ml) derived from Salmonella enteritidis decreased rate of firing of spontaneous action potentials in HL-1 cells, and it increased their pacemaker potential durations and decreased their rates of depolarization, all measured by whole cell current clamp. LPS also increased action potential durations and decreased their amplitude in cells paced at 1 Hz with 0.1 nA, and 20 min were necessary for maximal effect. LPS decreased the amplitude of a rapidly inactivating inward current attributed to Na ϩ and of an outward current attributed to K ϩ ; both were measured by whole cell voltage clamp. The K ϩ currents displayed a resurgent outward tail current, which is characteristic of the rapid delayed-rectifier K ϩ current, IKr. LPS accordingly reduced outward currents measured with pipette Cs ϩ substituted for K ϩ to isolate IKr. E-4031 (1 M) markedly inhibited IKr in HL-1 cells and also increased action potential duration; however, the direct effects of E-4031 occurred minutes faster than the slow effects of LPS. We conclude that LPS increases action potential duration in HL-1 mouse cardiomyocytes by inhibition of IKr and decreases their rate of firing by inhibition of INa. This protracted time course points toward an intermediary metabolic event, which either decreases available mouse ether-a-go-go (mERG) and Na ϩ channels or potentiates their inactivation.delayed rectifier K ϩ current; patch-clamp electrophysiology; Salmonella enteritidis; E-4031 SEPSIS IS A COMPLEX CLINICAL problem that can progress into multiorgan dysfunction syndrome (MODS) and death. At least one-half of the high mortality rates of severe-sepsis, sepsis, and MODS result from cardiovascular failure (27). Approximately 40% of patients in septic shock also experience myocardial dysfunction (36, 44), which comprises reduced systolic contractility, impaired diastolic relaxation, and ventricular dilatation. The initial clinical pattern, however, ironically is termed "hyperdynamic," because it often presents with high cardiac output, elevated heart rate, and vasodilatation of the dermis (27). This is attributable in part to the volume loading that is frequently the initial treatment for septic shock patients to maintain cardiac output and organ perfusion (15, 28). As is often the case in the complexity of sepsis, the prevailing symptoms can mask organ and system failure occurring at a deeper level in the clinical spectrum.The most prevalent sign of myocardial depressio...

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Section: Discussionsupporting

confidence: 91%

Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes

Wondergem

Graves

et al. 2012

American Journal of Physiology-Cell Physiology

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“…50,51 Furthermore, CLP does not reproducibly result in kidney injury. The absence of sepsis-associated comorbidities that are common in human patients and known to affect the immune system (e.g., old age, diabetes mellitus, and CKD) is also a limiting factor that needs to be considered in translating findings derived from the current models.…”

Section: Renal Ir Injurymentioning

confidence: 98%

Inflammation in AKI

Rabb

Griffin

McKay

et al. 2016

Journal of the American Society of Nephrology

432

343

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Inflammation is a complex biologic response that is essential for eliminating microbial pathogens and repairing tissue after injury. AKI associates with intrarenal and systemic inflammation; thus, improved understanding of the cellular and molecular mechanisms underlying the inflammatory response has high potential for identifying effective therapies to prevent or ameliorate AKI. In the past decade, much knowledge has been generated about the fundamental mechanisms of inflammation. Experimental work in small animal models has revealed many details of the inflammatory response that occurs within the kidney after typical causes of AKI, including insights into the molecular signals released by dying cells, the role of pattern recognition receptors, the diverse subtypes of resident and recruited immune cells, and the phased transition from destructive to reparative inflammation. Although this expansion of the basic knowledge base has increased the number of mechanistically relevant targets of intervention, progress in developing therapies that improve AKI outcomes by modulation of inflammation remains slow. In this article, we summarize the most important recent developments in understanding the inflammatory mechanisms of AKI, highlight key limitations of the commonly used animal models and clinical trial designs that may prevent successful clinical application, and suggest priority approaches for research toward clinical translation in this area.

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“…PC exerts its antiinflammatory function both by inhibiting thrombin generation and thus overriding downstream effects of the thrombin-induced proinflammatory response (22) and by signaling through EPCR in a PAR-1-dependent manner (23)(24)(25). PC also prevents inflammation by downregulating inflammatory signaling mediators, such as IL-6 (18,(26)(27)(28). Accordingly, various markers were measured to evaluate the resting inflammatory potential in these low-PC mice.…”

Section: Generation Of Transgenic Mice Expressing Very Low Levels Of Pcmentioning

confidence: 99%

“…However, mice with a targeted total deletion of the PC gene (PC -/-) do not survive the neonatal period (16), which thus prevents investigation of PC function in mature PC -/-mice. While heterozygous deficient PC mice (PC +/-) do survive the early lethality, live to adulthood, and can be successfully employed in some disease models (17,18), the approximately 50% level of PC in these mice is often too high to observe spontaneous phenotypes and is not reflective of symptomatic patients. Thus, we sought a manner of generating mice with a severe genetic PC deficiency via transgenic approaches.…”

Section: Introductionmentioning

confidence: 99%

Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities

Lay¹,

Zhong²,

Rosen³

et al. 2005

J. Clin. Invest.

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Anticoagulant protein C (PC) is important not only for maintenance of normal hemostasis, but also for regulating the host immune response during inflammation. Because mice with a designed total genetic deficiency in PC (PC -/-mice) die soon after birth, attempts to dissect PC function in various coagulation/inflammationbased pathologies through use of mice with less than 50% of normal PC levels have not been successful to date. In the current investigation, we have used a novel transgenic strategy to generate different mouse models expressing 1-18% of normal PC levels. In contrast to PC -/-mice, mice with only partial PC deficiency survived beyond birth and also developed thrombosis and inflammation. The onset and severity of these phenotypes vary significantly and are strongly dependent on plasma PC levels. Our findings additionally provide the first evidence that maternal PC is vital for sustaining pregnancy beyond 7.5 days postcoitum, likely by regulating the balance of coagulation and inflammation during trophoblast invasion. These low PC-expressing transgenic mouse lines provide novel animal models that can be used to elucidate the importance of PC in maintenance of the organism and in disease.

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A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model

Cited by 61 publications

References 76 publications

Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes

Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes

Inflammation in AKI

Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities

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