Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin

Abstract

Rationale: Dysregulated neutrophil functions with age and sepsis are described. Statins are associated with improved infection survival in some observational studies, but trials in critically ill patients have not shown benefit. Statins also alter neutrophil responses in vitro.Objectives: To assess neutrophil migratory accuracy with age during respiratory infections and determine if and how a statin intervention could alter these blunted responses.Methods: The migratory accuracy of blood neutrophils from young (aged ,35 yr) and old (aged .60 yr) patients in health and during a lower respiratory tract infection, community-acquired pneumonia, and pneumonia associated with sepsis was assessed with and without simvastatin. In vitro results were confirmed in a double-blind randomized clinical trial in healthy elders. Cell adhesion markers were assessed. Measurements and Main Results:In vitro neutrophil migratory accuracy in the elderly deteriorated as the severity of the infectious pulmonary insult increased, without recovery at 6 weeks. Simvastatin rescued neutrophil migration with age and during mild to moderate infection, at high dose in older adults, but not during more severe sepsis. Confirming in vitro results, high-dose (80-mg) simvastatin improved neutrophil migratory accuracy without impeding other neutrophil functions in a double-blind randomized clinical trial in healthy elders. Simvastatin modified surface adhesion molecule expression and activity, facilitating accurate migration in the elderly.Conclusions: Infections in older adults are associated with prolonged, impaired neutrophil migration, potentially contributing to poor outcomes. Statins improve neutrophil migration in vivo in health and in vitro in milder infective events, but not in severe sepsis, supporting their potential utility as an early intervention during pulmonary infections.Clinical trial registered with www.clinicaltrialsregister.eu (2011-002082-38).

Friend or foe? The dual role of neutrophils in lung injury and repair

“…Furthermore, a number of neutrophil phenotypes have been identified in different experimental models, and these phenotypes seem to display different functional characteristics. For example, neutrophils have been described as senescent15 and immunosuppressive16 (thought to potentially contribute to the immunosuppression seen after sepsis17) although the physiological and pathological relevance of these phenotypes is as yet unclear. A neutrophil phenotype of potential relevance to the current study8 is the so-called ‘angiogenic neutrophil’; a subset which makes up 3% of neutrophils, identified by being CD49d + VEGFR1 high CXCR4 high and characterised by increased MMP-9 release 18…”

Statin Use Is Associated With Reduced Mortality On Mechanically Ventilated Patients: A Retrospective Propensity-Matched Analysis Of MIMIC-III Database

“…A recent study showed that infections in older adults were associated with prolonged, impaired neutrophil migration. Simvastatin improves neutrophil migration in vivo in healthy individuals and in vitro in milder infective events but not in severe sepsis, supporting its potential utility as an early intervention during pulmonary infections [27,28].…”

Simvastatin preparations promote PDGF‐BB secretion to repair LPS‐induced endothelial injury through the PDGFRβ/PI3K/Akt/IQGAP1 signalling pathway

“…Statins, hydroxymethylglutaryl‐CoA reductase inhibitors, may have effects on inflammatory diseases such as sepsis and ARDS via its multiple properties, including an anti‐inflammatory effect and inhibition of leucocyte adhesion . Statins have become a controversial treatment for sepsis and infectious diseases in recent years . Due to the poor water solubility and strong fat solubility of statins, NP carrier systems have been designed to enhance drug delivery, and it has been confirmed that SV‐NPs have good efficacy towards chronic inflammatory disorders such as atherosclerosis and chronic pulmonary disease .…”

“…35,36 Statins have become a controversial treatment for sepsis and infectious diseases in recent years. [36][37][38][39][40] Due to the poor water solubility and strong fat solubility of statins, NP carrier systems have been designed to enhance drug delivery, 41 and it has been confirmed that SV-NPs have good efficacy towards chronic inflammatory disorders such as atherosclerosis and chronic pulmonary disease. 29,42 The formulation of SV-NPs improves the pharmacokinetic profile and bioavailability of SV 43 ; it was also reported that nanostructured lipid carriers, especially those associated with SV, were able to reduce cytotoxicity.…”