The renin-angiotensin system (RAS) conceived as a coordinated hormonal cascade plays an important role in controlling multiple functions in many organs and is much more complex than previously thought. The RAS has continued to expand, with the identification of new components, functions and subsystems. Angiotensin-converting enzyme (ACE) and its novel homolog angiotensin converting enzyme 2 (ACE2) are two key enzymes involved in the synthesis of bioactive components of the RAS. The main active peptides of the RAS include angiotensin II (Ang II), Ang III, Ang IV, and angiotensin-(1-7) [Ang-(1-7)] among which Ang II and Ang-(1-7) are much more important in health and disease. The axis formed by ACE2 represents an endogenous counter-regulatory pathway within the RAS, and its actions are opposite to those of the ACE axis. Conventionally the RAS has been considered to be important in the cardiovascular system, metabolism, cell growth and homeostasis. In recent years, a key role of ACE and ACE2 and their peptides has been recognized in the inflammatory process in conditions such as cardiac hypertrophy, pulmonary hypertension, glomerulonephritis, lung injury, sepsis, and acute pancreatitis. Investigations are ongoing to better understand the role of the RAS in inflammation. A comprehensive understanding of the RAS components in inflammation can provide new possibilities for therapeutic approaches against inflammatory diseases. In this review, we discuss our current understanding of the subject, based on recent findings, on the role of ACE and ACE2 in inflammation.

No abstract

BackgroundHydrogen sulfide (H2S), produced by the activity of cystathionine-gamma-lyase (CSE), is a key mediator of inflammation in sepsis. The liver sinusoidal endothelial cells (LSECs) are important target and mediator of sepsis. The aim of this study was to investigate the role of CSE-derived H2S on inflammation and LSECs fenestrae in caecal-ligation and puncture (CLP)-induced sepsis using CSE KO mice.MethodsSepsis was induced by CLP, and mice (C57BL/6J, male) were sacrificed after 8 hours. Liver, lung, and blood were collected and processed to measure CSE expression, H2S synthesis, MPO activity, NF-κB p65, ERK1/2, and cytokines/chemokines levels. Diameter, frequency, porosity and gap area of the liver sieve were calculated from scanning electron micrographs of the LSECs.ResultsAn increased CSE expression and H2S synthesizing activity in the liver and lung of wild-type mice following CLP-induced sepsis. This was associated with an increased liver and lung MPO activity, and increased liver and lung and plasma levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and the chemokines MCP-1 and MIP-2α. Conversely, CSE KO mice had less liver and lung injury and reduced inflammation following CLP-induced sepsis as evidenced by decreased levels of H2S synthesizing activity, MPO activity, and pro-inflammatory cytokines/chemokines production. Extracellular-regulated kinase (ERK1/2) and nuclear factor-κB p65 (NF-κB) became significantly activated after the CLP in WT mice but not in CSE KO mice. In addition, CLP-induced damage to the LSECs, as indicated by increased defenestration and gaps formation in the LSECs compared to WT sham control. CSE KO mice showed decreased defenestration and gaps formation following sepsis.ConclusionsMice with CSE (an H2S synthesising enzyme) gene deletion are less susceptible to CLP-induced sepsis and associated inflammatory response through ERK1/2-NF-κB p65 pathway as evidenced by reduced inflammation, tissue damage, and LSECs defenestration and gaps formation.

No abstract

Hydrogen sulphide is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in macrophages. To determine the role of H2S and macrophages in sepsis, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of sepsis. Cecal ligation puncture (CLP)-induced sepsis is characterized by increased levels of myeloperoxidase (MPO) activity, morphological changes in liver and pro-inflammatory cytokines and chemokines in the liver and lung. SiRNA treatment attenuated inflammation in the liver and lungs of mice following CLP-induced sepsis. Liver MPO activity increased in CLP-induced sepsis and treatment with siRNA significantly reduced this. Similarly, lung MPO activity increased following induction of sepsis with CLP while siRNA treatment significantly reduced MPO activity. Liver and lung cytokine and chemokine levels in CLP-induced sepsis reduced following treatment with siRNA. These findings show a crucial pro-inflammatory role for H2S synthesized by CSE in macrophages in sepsis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition.