Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock

Temmesfeld-Wollbrück, Bettina; Brell, Bernhard; Dávid, István; Dorenberg, Martin; Adolphs, Jörn; Schmeck, Bernd; Suttorp, Norbert; Hippenstiel, Stefan

doi:10.1007/s00134-007-0561-y

Cited by 88 publications

(78 citation statements)

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“…Furthermore, inflammatory conditions such as sepsis or acute lung injury increased adrenomedullin expression [67][68][69], and the inflammatory response and organ damage in mice heterozygous for the adrenomedullin gene were aggravated upon LPS challenge [70]. Treatment with exogenous adrenomedullin improved pulmonary barrier dysfunction caused by different stimuli such as hydrogen peroxide, LPS or Staphylococcus aureus α-toxin and was protective against ventilator-induced lung injury in mice with and without pneumonia [61,[71][72][73][74]. At least two major mechanisms underlie the barrier-protective effect of adrenomedullin: 1) reducing actin-myosin-based endothelial cell contraction [62] and 2) strengthening intercellular adherence junctions [75,76].…”

Section: Improving Pulmonary Barrier Functionmentioning

confidence: 99%

Therapeutic strategies in pneumonia: going beyond antibiotics

et al. 2015

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Dysregulation of the innate immune system drives lung injury and its systemic sequelae due to breakdown of vascular barrier function, harmful hyperinflammation and microcirculatory failure, which contribute to the unfavourable outcome of patients with severe pneumonia. A variety of promising therapeutic targets have been identified and numerous innovative therapeutic approaches demonstrated to improve lung injury in experimental preclinical studies. However, at present specific preventive or curative strategies for the treatment of lung failure in pneumonia in addition to antibiotics are still missing. The aim of this mini-review is to give a short overview of some, but not all, adjuvant therapeutic strategies for pneumonia and its most important complications, sepsis and acute respiratory distress syndrome, and briefly discuss future perspectives. @ERSpublications A review of preclinical and clinical research on adjuvant therapies for pneumonia

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Section: Improving Pulmonary Barrier Functionmentioning

confidence: 99%

Therapeutic strategies in pneumonia: going beyond antibiotics

et al. 2015

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“…AM has also been shown to reduce TNF-α expression and release in macrophage cell lines and rat Kupffer cells [33]. More recently, administration of AM to rats with α-toxin-induced sepsis reduced vascular hyperpermeability and resulted in dramatically improved survival rates [31]. Finally, dynamic and robust changes in the expression of AM and its receptors occur in the lungs in response to septic shock [4,22].…”

Section: Introductionmentioning

confidence: 99%

Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock

Dackor

Caron

2007

Peptides

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Adrenomedullin (AM) is a highly conserved peptide that can act as a potent vasodilator, antimicrobial factor and anti-inflammatory factor. Several studies have implicated diverse roles for AM in regulating the inflammatory and hemodynamic responses to septic shock. Moreover, during sepsis the receptors that mediate AM signaling [calcitonin receptor-like receptor (calcrl) and receptor activity modifying proteins (RAMP) 2 and 3] undergo dynamic and robust changes in their expression. Although numerous studies have used animal models to study the role of administered or increased AM in septic animals, genetic studies to determine the consequences of reduced AM during septic shock have not yet been performed. Here, we used a murine model of lipopolysaccharide (LPS)-induced septic shock to assess the inflammatory response in mice heterozygous for the AM gene. Following LPS challenge, AM +/− mice had higher expression of TNF-α and IL-1β than LPS-treated wild-type (WT) controls. Consequently, serum TNF-α was also significantly elevated in LPS-treated AM +/− mice compared to WT LPS-treated mice. We also observed higher serum levels of liver enzymes, suggesting more advanced end-organ damage in mice with genetically reduced AM. Finally, we found that RAMP2 and calcrl expression levels were markedly reduced in LPS-treated mice, whereas RAMP3 expression was significantly elevated. Importantly, these changes in receptor gene expression were conserved in AM +/− mice, demonstrating that AM peptide itself does not impact directly on the expression of the genes encoding its receptors. We therefore conclude that during septic shock the dynamic modulation of AM and its receptors primarily functions to dampen the inflammatory response.

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“…1 Adrenomedullin is a peptide produced by multiple tissue types during physiologic stress, and has pluripotent function, including vasodilatory, antimicrobial, and antiinflammatory activity. 2 In animal models of sepsis, [3][4][5] exogenous adrenomedullin reduces acute lung injury, vascular permeability, and death; endogenous overexpression similarly ameliorates the septic insult. Human data are sparse, but early studies 6,7 reported high adrenomedullin levels associated with increased vasodilation and severity of illness in systemic inflammation and septic shock.…”

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Midregional Proadrenomedullin as a Prognostic Tool in Community-Acquired Pneumonia

Huang

Angus

Kellum

et al. 2009

Chest

124

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Background: Midregional proadrenomedullin (MR-proADM) is a potential prognostic biomarker in patients with community-acquired pneumonia (CAP). Previous work has been hampered by sample size and illness spectrum limits. We sought to describe the pattern of MR-proADM in a broad CAP cohort, confirm its prognostic role, and compare its performance to procalcitonin, a novel biomarker of infection. Methods: We conducted a multicenter prospective cohort study in 28 community and teaching EDs. Patients with a clinical and radiographic diagnosis of CAP were enrolled. We stratified MR-proADM levels a priori into quartiles and quantified severity of illness using the pneumonia severity index (PSI); and confusion (abbreviated mental test score of < 8), urea > 7 mmol/L, respiratory rate > 30 breaths/min, BP < 90 mm Hg systolic or < 60 mm Hg diastolic, age > 65 years (CURB-65). The primary outcome was 30-day mortality. Results: A total of 1,653 patients formed the study cohort. MR-proADM levels consistently rose with PSI class and 30-day mortality (p < 0.001). MR-proADM had a higher area under the curve for 30-day mortality than procalcitonin (0.76 vs 0.65, respectively; p < 0.001), but adding MR-proADM to the PSI in all subjects minimally improved performance. Among low-risk subjects (PSI classes I to III), mortality was low and did not differ by MR-proADM quartile. However, among high-risk subjects (PSI class IV/V; n ‫؍‬ 546), subjects in the highest MR-proADM quartile (n ‫؍‬ 232; 42%) had higher 30-day mortality than those in MR-proADM quartiles 1 to 3 (23% vs 9%, respectively; p < 0.0001). Similar results were seen with CURB-65. MR-proADM and procalcitonin levels were generally concordant; only 6% of PSI class IV/V subjects in the highest MR-proADM quartile had very low procalcitonin levels (< 0.1 ng/mL). Conclusions: In our multicenter CAP cohort, MR-proADM levels correlate with increasing severity of illness and death. High MR-proADM levels offer additional risk stratification in high-risk CAP patients, but otherwise MR-proADM levels do not alter PSI-based risk assessment in most CAP patients.(CHEST 2009; 136:823-831)

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Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock

Abstract: These data suggest that adrenomedullin-related reduction of vascular hyperpermeability might represent a novel and important mechanism contributing to the beneficial effects of this endogenous vasoregulatory peptide in sepsis and septic shock.

Cited by 88 publications

References 43 publications

Therapeutic strategies in pneumonia: going beyond antibiotics

Therapeutic strategies in pneumonia: going beyond antibiotics

Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock

Midregional Proadrenomedullin as a Prognostic Tool in Community-Acquired Pneumonia

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