Local Shwartzman Reaction in the Rat Induced by Endotoxin and Ischemia: Potential Model for Skin Necrosis in Meningococcemia

Penington, Anthony; Craft, Randall O.; Mitchell, Geraldine M.; Morrison, Wayne A.

doi:10.1203/01.pdr.0000228326.99650.19

Cited by 5 publications

(3 citation statements)

References 8 publications

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“…The most important skin pathologic findings in the experimental cutaneous Shwartzman are vastly skin necrosis, vascular thrombosis, hemorrhage, and infiltration of leukocytes, especially neutrophils, into the site of inflammation 3,7,27 . In the current study, skin pathologic findings showed a slight skin necrosis and neutrophils recruitment in group treated with 100 pmol of trimer aptamer (Figure 7(a)).…”

Section: Resultssupporting

confidence: 54%

A cross‐linked anti‐TNF‐α aptamer for neutralization of TNF‐α‐induced cutaneous Shwartzman phenomenon: A simple and novel approach for improving aptamers' affinity and efficiency

Mashayekhi

Sankian

Haftcheshmeh

et al. 2021

Biotechnology Progress

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To increase the efficiency of aptamers to their targets, a simple and novel method has been developed based on aptamer oligomerization. To this purpose, previously anti‐human TNF‐α aptamer named T1–T4 was trimerized through a trimethyl aconitate core for neutralization of in vitro and in vivo of TNF‐α. At first, 54 mer T1–T4 aptamers with 5′‐NH2 groups were covalently coupled to three ester residues in the trimethyl aconitate. In vitro activity of novel anti‐TNF‐α aptamer and its dissociation constant (Kd) was done using the L929 cell cytotoxicity assay. In vivo anti‐TNF‐α activity of new oligomerized aptamer was assessed in a mouse model of cutaneous Shwartzman. Anchoring of three T1–T4 aptamers to trimethyl aconitate substituent results in formation of the 162 mer fragment, which was well revealed by gel electrophoresis. In vitro study indicated that the trimerization of T1–T4 aptamer significantly improved its anti‐TNF‐α activity compared to non‐modified aptamers (P < 0.0001) from 40% to 60%. The determination of Kd showed that trimerization could effectively enhance Kd of aptamer from 67 nM to 36 nM. In vivo study showed that trimer aptamer markedly reduced mean scar size from 15.2 ± 1.2 mm to 1.6 ± 0.1 mm (P < 0.0001), which prevent the formation of skin lesions. In vitro and in vivo studies indicate that trimerization of anti‐TNF‐α aptamer with a novel approach could improve the anti‐TNF‐α activity and therapeutic efficacy. According to our findings, a new anti‐TNF‐α aptamer described here could be considered an appropriate therapeutic agent in treating several inflammatory diseases.

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Section: Resultssupporting

confidence: 54%

A cross‐linked anti‐TNF‐α aptamer for neutralization of TNF‐α‐induced cutaneous Shwartzman phenomenon: A simple and novel approach for improving aptamers' affinity and efficiency

Mashayekhi

Sankian

Haftcheshmeh

et al. 2021

Biotechnology Progress

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“…The pathogenic effects of meningococcemia, particularly on the skin have previously been attributed to circulating LPS [1], [33], [34]. In this model, non-adherent bacteria, despite circulating in the same numbers as the wild type strain and thus releasing similar amounts of LPS and other bacterial compounds, do not trigger cytokine secretion in the human tissue or lead to significant vascular damage.…”

Section: Discussionmentioning

confidence: 90%

Adhesion of Neisseria meningitidis to Dermal Vessels Leads to Local Vascular Damage and Purpura in a Humanized Mouse Model

et al. 2013

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Septic shock caused by Neisseria meningitidis is typically rapidly evolving and often fatal despite antibiotic therapy. Further understanding of the mechanisms underlying the disease is necessary to reduce fatality rates. Postmortem samples from the characteristic purpuric rashes of the infection show bacterial aggregates in close association with microvessel endothelium but the species specificity of N. meningitidis has previously hindered the development of an in vivo model to study the role of adhesion on disease progression. Here we introduced human dermal microvessels into SCID/Beige mice by xenografting human skin. Bacteria injected intravenously exclusively associated with the human vessel endothelium in the skin graft. Infection was accompanied by a potent inflammatory response with the secretion of human inflammatory cytokines and recruitment of inflammatory cells. Importantly, infection also led to local vascular damage with hemostasis, thrombosis, vascular leakage and finally purpura in the grafted skin, replicating the clinical presentation for the first time in an animal model. The adhesive properties of the type IV pili of N. meningitidis were found to be the main mediator of association with the dermal microvessels in vivo. Bacterial mutants with altered type IV pili function also did not trigger inflammation or lead to vascular damage. This work demonstrates that local type IV pili mediated adhesion of N. meningitidis to the vascular wall, as opposed to circulating bacteria, determines vascular dysfunction in meningococcemia.

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“…The study suggested that the bacterial infection can sensitize tissues to the effects of ischemia, effectively lowering the threshold to acquiring irreversible cell injury (see Table 2). 75 The "two-hit" experimental model of sepsis, DIC, and netosis…”

Section: Pathophysiology Of the Shwartzman-like Reactionmentioning

confidence: 99%

Whatever happened to the Shwartzman phenomenon?

Chahin

Opal

2018

Innate Immun

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Ninety years ago, Gregory Shwartzman first reported an unusual discovery following the intradermal injection of sterile culture filtrates from principally Gram-negative strains from bacteria into normal rabbits. If this priming dose was followed in 24 h by a second intravenous challenge (the provocative dose) from same culture filtrate, dermal necrosis at the first injection site would regularly occur. This peculiar, but highly reproducible, event fascinated the microbiologists, hematologists, and immunologists of the time, who set out to determine the mechanisms that underlie the pathogenesis of this reaction. The speed of this reaction seemed to rule out an adaptive, humoral, immune response as its cause. Histopathologic material from within the necrotic center revealed fibrinoid, thrombo-hemorrhagic necrosis within small arterioles and capillaries in the micro-circulation. These pathologic features bore a striking resemblance to a more generalized coagulopathic phenomenon following two repeated endotoxin injections described 4 yr earlier by Sanarelli. This reaction came to be known as the generalized Shwartzman phenomenon, while the dermal reaction was named the localized or dermal Shwartzman reaction. A third category was later added, called the single organ or mono-visceral form of the Shwartzman phenomenon. The occasional occurrence of typical pathological features of the generalized Shwartzman reaction limited to a single organ is notable in many well-known clinical events (e.g., hyper-acute kidney transplant rejection, fulminant hepatic necrosis, or adrenal apoplexy in Waterhouse-Fredrickson syndrome). We will briefly review the history and the significant insights gained from understanding this phenomenon regarding the circuitry and control mechanisms responsible for disseminated intravascular coagulation, the vasculopathy and the immunopathy of sepsis.

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Local Shwartzman Reaction in the Rat Induced by Endotoxin and Ischemia: Potential Model for Skin Necrosis in Meningococcemia

Cited by 5 publications

References 8 publications

A cross‐linked anti‐TNF‐α aptamer for neutralization of TNF‐α‐induced cutaneous Shwartzman phenomenon: A simple and novel approach for improving aptamers' affinity and efficiency

A cross‐linked anti‐TNF‐α aptamer for neutralization of TNF‐α‐induced cutaneous Shwartzman phenomenon: A simple and novel approach for improving aptamers' affinity and efficiency

Adhesion of Neisseria meningitidis to Dermal Vessels Leads to Local Vascular Damage and Purpura in a Humanized Mouse Model

Whatever happened to the Shwartzman phenomenon?

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