Role of Toll-Like Receptors in the Development of Sepsis

Tsujimoto, Hironori; Ono, Satoshi; Efron, Philip A.; Scumpia, Philip O.; Moldawer, Lyle L.; Mochizuki, Hidetaka

doi:10.1097/shk.0b013e318157ee55

Cited by 210 publications

(162 citation statements)

References 93 publications

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“…The binding of PAMPs with particular receptors on the cell surface activates an intracellular cascade [2,3]. This results in up-or down-regulation of specific genes encoding for a variety of proteins including cytokines and other inflammatory mediators and receptors [4].…”

Section: Pamps and Dampsmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer²

2013

Current Vascular Pharmacology

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Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production. In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated. As a result, cells and organs may survive in a non-functioning hibernation-like condition. Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown. Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors. Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins. All these changes are mediated by cytokines. Treatment includes preload optimization with sufficient fluids. However, excessive volume loading is harmful. The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines. During early sepsis, cardiac output can be increased by dobutamine. While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful. Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice. While early administration of catecholamines might be necessary to restore adequate organ perfusion and pressure, prolonged administration might be harmful.Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine will reduce myocardial oxygen expenditure and ameliorate diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. However, all these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice.-3 -Alain Rudiger & Mervyn Singer: The heart in sepsis

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Section: Pamps and Dampsmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer²

2013

Current Vascular Pharmacology

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“…(10)(11)(12) TLR stimulation by lipopolysaccharide (LPS), a causative factor of sepsis, activated CYP27B1 expression in human macrophages. (13,14) Moreover, the liver is the organ that contains the greatest number of macrophages. (15) Thus we anticipated that the liver-resident macrophages, namely, Kupffer cells, are the main cause of extrarenal 1a-hydroxylation of 25(OH)D in these patients.…”

Section: Discussionmentioning

confidence: 99%

A patient with severe hypercalcemia in multiple organ dysfunction syndrome: Role of elevated circulating 1α,25(OH)2vitamin D levels

Kazama

Yamamoto

Oya

et al. 2010

Journal of Bone and Mineral Research

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A 54-year-old man was transferred to our ICU because of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). He died after 38 days of intensive care. During treatment, his serum calcium (Ca) levels continued to increase and reached 3.95 mmol/L, while the ionized Ca levels reached 2.30 mmol/L before his death. He presented with severe kidney injury, pancreatitis, and hemorrhagic gastric erosion that worsened his prognosis; these were possibly associated with the hypercalcemia. His circulating 1a,25-dihydroxyvitamin D [1,25(OH) 2 D] level was elevated (75.7 to 204 pg/mL), whereas the levels of 25-hydroxyvitamin D, parathyroid hormone, and parathyroid hormone-related peptide were not. Liver histology revealed immunoreactivity for 25-hydroxyvitamin D 1a-hydroxylase (CYP27B1) in some of the hepatocytes, in which the localization pattern was similar to that of lysozyme-positive hepatocytes. Our ICU has previously encountered 22 similar MODS patients who presented with hypercalcemia over the last 8 years. SIRS with severe kidney and liver injuries are common clinical findings in hypercalcemic patients with MODS. Of the 23 hypercalcemic MODS patients, including the present patient, 17 had circulating 1,25(OH) 2 D levels exceeding 70 pg/mL despite severe kidney injury. Extrarenal activation of CYP27B1 seems to play a role in the development of hypercalcemia in this disease condition. Clinicians need to be aware that severe hypercalcemia may occur in MODS patients. ß

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“…Toll-like receptors are a subgroup of PRRs and play an important role in host defence against invading microorganisms during sepsis [70][71][72]. In an animal model of pneumococcal pneumonia, triggering of TLR-5 with its ligand, flagellin, leads to substantially improved survival [73].…”

Section: Toll-like Receptor Antagonistsmentioning

confidence: 99%