Micro-management: curbing chronic wound infection

Chronic wounds, including pressure ulcers, foot ulcers and venous leg ulcers have a detrimental impact on the health and well-being of an estimated 2% of people in the UK. Chronic wounds are normally colonised by bacteria and in some instances bacterial load increases sufficiently for infection to ensue. Once a chronic wound becomes infected it is difficult to resolve and a combination of continuous inflammation and bacterial proliferation makes these wounds difficult to manage. A state of prolonged inflammation can occur as a result of impaired homeostatic pathways which are exacerbated by bacterial growth. Chronic, infected wounds can persist for many months or even years, sometimes requiring surgical intervention in the form of regular debridement or amputation when other strategies such as antimicrobial treatments fail. The complex relationships between both oral microbiota and the host have been extensively characterised, including the shift from health to disease, and has allowed for the development of numerous control strategies. This knowledge combined with contemporary studies of chronic infected wounds can be used to develop an understanding of the relationship between the host and microorganism in the chronic wound environment. Such information has the potential to inform wound management including strategies to control infection and promote wound healing

Evolution of metabolic divergence in <i>Pseudomonas aeruginosa</i> during long-term infection facilitates a proto-cooperative interspecies interaction

The effect of polymicrobial interactions on pathogen physiology and how it can act either to limit pathogen colonization or to potentiate pathogen expansion and virulence are not well understood. Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic pathogens commonly found together in polymicrobial human infections. However, we have previously shown that the interactions between these two bacterial species are strain dependent. Whereas P. aeruginosa PAO1, a commonly used laboratory strain, effectively suppressed S. aureus growth, we observed a commensal-like interaction between the human host-adapted strain, DK2-P2M24-2003, and S. aureus. In this study, characterization by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) imaging mass spectrometry (IMS) and mass spectral (MS) molecular networking revealed a significant metabolic divergence between P. aeruginosa PAO1 and DK2-P2M24-2003, which comprised several virulence factors and signaling 4-hydroxy-2-alkylquinoline (HAQ) molecules. Strikingly, a further modulation of the HAQ profile was observed in DK2-P2M24-2003 during interaction with S. aureus, resulting in an area with thickened colony morphology at the P. aeruginosa–S. aureus interface. In addition, we found an HAQ-mediated protection of S. aureus by DK2-P2M24-2003 from the killing effect of tobramycin. Our findings suggest a model where the metabolic divergence manifested in human host-adapted P. aeruginosa is further modulated during interaction with S. aureus and facilitate a proto-cooperative P. aeruginosa–S. aureus relationship

C to U editing at position 32 of the anticodon loop precedes tRNA 5′ leader removal in trypanosomatids

In all organisms, precursor tRNAs are processed into mature functional units by post-transcriptional changes. These involve 5′ and 3′ end trimming as well as the addition of a significant number of chemical modifications, including RNA editing. The only known example of non-organellar C to U editing of tRNAs occurs in trypanosomatids. In this system, editing at position 32 of the anticodon loop of tRNAThr(AGU) stimulates, but is not required for, the subsequent formation of inosine at position 34. In the present work, we expand the number of C to U edited tRNAs to include all the threonyl tRNA isoacceptors. Notably, the absence of a naturally encoded adenosine, at position 34, in two of these isoacceptors demonstrates that A to I is not required for C to U editing. We also show that C to U editing is a nuclear event while A to I is cytoplasmic, where C to U editing at position 32 occurs in the precursor tRNA prior to 5′ leader removal. Our data supports the view that C to U editing is more widespread than previously thought and is part of a stepwise process in the maturation of tRNAs in these organisms

Probiotics or pro-healers: the role of beneficial bacteria in tissue repair

Probiotics are beneficial microorganisms, known to exert numerous positive effects on human health, primarily in the battle against pathogens. Probiotics have been associated with improved healing of intestinal ulcers, and healing of infected cutaneous wounds. This article reviews the latest findings on probiotics related to their pro-healing properties on gut epithelium and skin. Proven mechanisms by which probiotic bacteria exert their beneficial effects include direct killing of pathogens, competitive displacement of pathogenic bacteria, reinforcement of epithelial barrier, induction of fibroblasts, and epithelial cells' migration and function. Beneficial immunomodulatory effects of probiotics relate to modulation and activation of intraepithelial lymphocytes, natural killer cells, and macrophages through induced production of cytokines. Systemic effects of beneficial bacteria and link between gut microbiota, immune system, and cutaneous health through gut-brain-skin axes are discussed as well. In light of growing antibiotic resistance of pathogens, antibiotic use is becoming less effective in treating cutaneous and systemic infections. This review points to a new perspective and therapeutic potential of beneficial probiotic species as a safe alternative approach for treatment of patients affected by wound healing disorders and cutaneous infections.This is the peer reviewed version of the paper: Lukic, J., Chen, V., Strahinic, I., Begovic, J., Lev-Tov, H., Davis, S. C., Tomic-Canic, M., & Pastar, I. (2017). Probiotics or pro-healers: The role of beneficial bacteria in tissue repair. Wound Repair and Regeneration, 25(6), 912–922. [https://doi.org/10.1111/wrr.12607

Photodynamic Therapy in Dermatology: Current Treatments and Implications

This article provides an update on photodynamic therapy by discussing each of the essential components in sequence: mechanisms of action, common photosensitizers, typical light sources, and indications. In dermatology, photodynamic therapy (PDT) is mainly used in the treatment of superficial skin cancers: actinic keratoses, Bowen’s disease and superficial basal cell carcinomas. However, the range of indications has been expanding continuously. PDT is also used for the treatment of other oncological indications and non-malignant conditions such as acne vulgaris and photoaged skin. The 5-aminolevulinic acid (ALA) or its methyl ester (MAL) is applied topically as photosensitizer before activation with visible light. The advantages of topical PDT are: ability to treat multiple lesions simultaneously, low invasiveness, good tolerance and excellent cosmetic results

Fluorescent cell tracer dye permits real-time assessment of re-epithelialization in a serum-free ex vivo human skin wound assay

YesEx vivo wounded human skin organ culture is an invaluable tool for translationally relevant preclinical wound healing research. However, studies incorporating this system are still underutilized within the field because of the low throughput of histological analysis required for downstream assessment. In this study, we use intravital fluorescent dye to lineage trace epidermal cells, demonstrating that wound re‐epithelialization of human ex vivo wounds occurs consistent with an extending shield mechanism of collective migration. Moreover, we also report a relatively simple method to investigate global epithelial closure of explants in culture using daily fluorescent dye treatment and en face imaging. This study is the first to quantify healing of ex vivo wounds in a longitudinal manner, providing global assessments for re‐epithelialization and tissue contraction. We show that this approach can identify alterations to healing with a known healing promoter. This methodological study highlights the utility of human ex vivo wounds in enhancing our understanding of mechanisms of human skin repair and in evaluating novel therapies to improve healing outcome.University of Manchester Strategic Fund; Wellcome Trust; BBSRC; Ministry of Higher Education, Malaysia Universiti; Sains Malaysi

Use of native type i collagen matrix plus polyhexamethylene biguanide for chronic wound treatment

© 2019 Lippincott Williams and Wilkins.All right reserved. Background: Chronic wounds represent a significant financial burden to the healthcare system and a quality-of-life burden to patients. Many chronic wounds have elevated bioburden in the form of biofilm, which has been associated with delayed wound healing. This study examined the use of a native type I collagen matrix with the antimicrobial polyhexamethylene biguanide (PCMP) in the management of bioburden and treatment of chronic, nonhealing wounds over 12 weeks. Methods: A prospective case series of PCMP enrolled adults ≥18 years old with a nonhealing wound. At week 0, the wound was prepared by sharp or mechanical debridement. Patients received standard wound care plus PCMP applications at week 0 and then weekly up to week 12 at the investigator\u27s discretion. Dressings were applied over PCMP to fix it in place. At each visit, wounds were assessed for the extent of healing and signs of wound infection. Results: Of the 41 wounds studied, 44% were pressure ulcers, 22% were surgical wounds, 12% were venous ulcers, 10% were diabetic ulcers, and 12% were another type. The median (interquartile range) baseline wound area was 7.2 (14.9) cm 2 , and the mean wound duration was 103 weeks. Of the 41 wounds, 73% demonstrated a reduction in wound area at 12 weeks, and 37% achieved complete wound closure, with a mean time of 6.7 weeks to complete closure. Conclusion: PCMP treatment appeared to positively impact the course of wound healing in a variety of complex, chronic wounds that were unresponsive to prior treatment

Innate immunity and microbial dysbiosis in hidradenitis suppurativa – vicious cycle of chronic inflammation

Hidradenitis Suppurativa (HS) is a chronic multifactorial inflammatory skin disease with incompletely understood mechanisms of disease pathology. HS is characterized by aberrant activation of the innate immune system, resulting in activation of pathways that aim to protect against pathogenic microorganisms, and also contribute to failure to resolve inflammation. Imbalance in innate immunity is evident in deregulation of host antimicrobial peptides (AMPs) and the complement system associated with the microbiome dysbiosis. The pathology is further complicated by ability of pathogens associated with HS to overcome host immune response. Potential roles of major AMPs, cathelicidin, defensins, dermcidin, S100 proteins, RNAse 7 and complement proteins are discussed. Dysregulated expression pattern of innate immunity components in conjunction with bacterial component of the disease warrants consideration of novel treatment approaches targeting both host immunity and pathogenic microbiome in HS

Angiogenin released from ABCB5+ stromal precursors improves healing of diabetic wounds by promoting angiogenesis

Severe angiopathy is a major driver for diabetes-associated secondary complications. Knowledge on the underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5+ stromal precursors at the edge of nonhealing diabetic wounds in a murine db/db model, closely mirroring human type 2 diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5+ stromal precursors. This compensates for the profoundly reduced angiogenin expression in nontreated murine chronic diabetic wounds. Silencing of angiogenin in ABCB5+ stromal precursors before injection significantly reduced angiogenesis and delayed wound closure in diabetic db/db mice, implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining stromal precursors–based therapies of nonhealing diabetic foot ulcers and other pathologies with impaired angiogenesis

Anti-inflammatory and cell proliferative effect of the 1270 nm laser irradiation on the BALB/c Nude mouse model involves activation of the cell antioxidant system

Recently, many interdisciplinary community researchers have focused their efforts on study of the low-level light irradiation effects (photobiomodulation, PBM) as a promising therapeutic technology. Among the priorities, a search of new wavelength ranges of laser radiation to enhance the laser prospects in treatment of autoimmune and cancer diseases commonly accompanied by disorders in the antioxidant system of the body. The laser wavelengths within 1265-1270 nm corresponds to the maximum oxygen absorption band. Therefore, PBM effects on a model organism within this spectrum range are of particular interest for preclinical research. Here, we report comprehensive biomolecular studies of the changes in the BALB/c nude mice skin after an exposure to the continuous laser radiation at the 1270 nm wavelength and energy densities of 0.12 and 1.2 J/cm2. Such regime induces both local and systemic PBM effects, presumably due to the short-term increase in ROS levels, which in turn activate the cell antioxidative system