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

Abstract

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.

A Monoclonal Antibody Against RAGE Alters Gene Expression and is Protective in Experimental Models of Sepsis and Pneumococcal Pneumonia

“…In a study of influenza, infection in murine lungs induced Tnfaip3, and overexpression attenuated NF-.B promoter activity in bronchial epithelial cells after infection (31). In a model of airway inflammation, the overexpression of Tnfaip3 decreased inflammation (30). Attenuation of lung inflammation through Socs3 expression or inhibition of NF-.BYrelated signaling pathways after treatment with the anti-RAGE antibody may partially explain the increased survival in that group and may offer a new therapeutic approach in sepsis.…”

“…The transcript encoding Tnfaip3 (A20) was increased in the anti-RAGEYtreated animals. Tnfaip3 is an inhibitor of NF-.B activation, and studies suggest that it is a negative regulator of inflammation (30). In a study of influenza, infection in murine lungs induced Tnfaip3, and overexpression attenuated NF-.B promoter activity in bronchial epithelial cells after infection (31).…”

Loss of receptor activity-modifying protein 3 exacerbates cardiac hypertrophy and transition to heart failure in a sex-dependent manner

“…Primer and probe sequences for detection of Ramp2, Ramp3 , Adm and Calcrl gene expression were previously described [25, 43]. For all other primers and probes, we used a pre-designed, Assays on Demand primer/probe set (Applied Biosystems).…”

Therapeutic strategies in pneumonia: going beyond antibiotics

“…The crucial role of adrenomedullin in protecting vascular barrier integrity was underscored by demonstrating that mice deficient in adrenomedullin, CRLR or other components of the adrenomedullin signalling pathway die prematurely due to hydrops fetalis [63][64][65][66]. 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].…”