title: DL-2-hydroxyisocaproic acid attenuates inflammatory responses in a murine Candida albicans biofilm model.
abstract: Chronic biofilm infections are often accompanied by a chronic inflammatory response, leading to impaired healing and increased, irreversible damage to host tissues. Biofilm formation is a major virulence factor for Candida albicans and a challenge for treatment. Most current antifungals have proved ineffective in eradicating infections attributed to biofilms. The biofilm structure protects Candida species against antifungals and provides a way for them to evade host immune systems. This leads to a very distinct inflammatory response compared to that seen in planktonic infections. Previously, we showed the superior efficacy of dl-2-hydroxyisocaproic acid (HICA) against various bacteria and fungi. However, the immunomodulatory properties of HICA have not been studied. Our aim was to investigate the potential anti-inflammatory response to HICA in vivo. We hypothesized that HICA reduces the levels of immune mediators and attenuates the inflammatory response. In a murine model, a robust biofilm was formed for 5 days in a diffusion chamber implanted underneath mouse skin. The biofilm was treated for 12 h with HICA, while caspofungin and phosphate-buffered saline (PBS) were used as controls. The pathophysiology and immunoexpression in the tissues surrounding the chamber were determined by immunohistochemistry. Histopathological examination showed an attenuated inflammatory response together with reduced expression of matrix metalloproteinase 9 (MMP-9) and myeloperoxidase (MPO) compared to those of chambers containing caspofungin and PBS. Interestingly, the expression of developmental endothelial locus 1 (Del-1), an antagonist of neutrophil extravasation, increased after treatment with HICA. Considering its anti-inflammatory and antimicrobial activity, HICA may have enormous therapeutic potential in the treatment of chronic biofilm infections and inflammation, such as those seen with chronic wounds.
authors.affiliation: Research Unit on Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland Departments of Periodontology and Oral and Maxillofacial Diseases, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland The University of Manchester, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, United Kingdom.
authors.forename: M T
authors.initials: MT
authors.lastname: Nieminen
authors.affiliation: Department of Oral Pathology and Medicine and Laboratory of Periodontal Biology, Faculty of Dentistry, Universidad de Chile, Santiago, Chile.
authors.forename: M
authors.initials: M
authors.lastname: Hernandez
authors.affiliation: The University of Manchester, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Novak-Frazer
authors.affiliation: Departments of Periodontology and Oral and Maxillofacial Diseases, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Kuula
authors.affiliation: Infection and Immunity Research Group, Glasgow Dental School and Hospital, School of Medicine, College of Medicine, Veterinary and Life Sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom.
authors.forename: G
authors.initials: G
authors.lastname: Ramage
authors.affiliation: The University of Manchester, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Bowyer
authors.affiliation: The University of Manchester, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Warn
authors.affiliation: Departments of Periodontology and Oral and Maxillofacial Diseases, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Sorsa
authors.affiliation: The University of Manchester, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, United Kingdom riina.richardson@manchester.ac.uk.
authors.forename: R
authors.initials: R
authors.lastname: Rautemaa
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D018441:Biofilms / Q000254:growth & development*; D002176:Candida albicans / Q000502:physiology*; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D002208:Caproates / Q000008:administration & dosage*; D004195:Disease Models, Animal; D006651:Histocytochemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007249:Inflammation / Q000473:pathology*; D008297:Male; D051379:Mice; D008853:Microscopy; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D002208:Caproates; D007166:Immunosuppressive Agents; C019419:alpha-hydroxyisocaproic acid