Oestrogen promotes healing in a bacterial LPS model of delayed cutaneous wound repair

Abstract

Wound infection is a major clinical problem, yet understanding of bacterial host interactions in the skin remains limited. Microbe-derived molecules, known as pathogen-associated molecular patterns, are recognised in barrier tissues by pattern-recognition receptors. In particular, the pathogen-associated molecular pattern, lipopolysaccharide (LPS), a component of microbial cell walls and a specific ligand for Toll-like receptor 4, has been widely used to mimic systemic and local infection across a range of tissues. Here we administered LPS derived from Klebsiella pneumoniae, a species of bacteria that is emerging as a wound-associated pathogen, to full-thickness cutaneous wounds in C57/BL6 mice. Early in healing, LPS-treated wounds displayed increased local apoptosis and reduced proliferation. Subsequent healing progression was delayed with reduced re-epithelialisation, increased proliferation, a heightened inflammatory response and perturbed wound matrix deposition. Our group and others have previously demonstrated the beneficial effects of 17β-estradiol treatment across a range of preclinical wound models. Here we asked whether oestrogen would effectively promote healing in our LPS bacterial infection model. Intriguingly, co-treatment with 17β-estradiol was able to promote re-epithelialisation, dampen inflammation and induce collagen deposition in our LPS-delayed healing model. Collectively, these studies validate K. pneumoniae-derived LPS treatment as a simple yet effective model of bacterial wound infection, while providing the first indication that oestrogen could promote cutaneous healing in the presence of infection, further strengthening the case for its therapeutic use.

Phenylboronic Acid Derivatives as Validated Leads Active in Clinical Strains Overexpressing KPC‐2: A Step against Bacterial Resistance

“…Under our experimental conditions, the K m value for nitrocefin measured for full-length KPC-2 was determined as 36.0 mm. [26,28,29] The K i values for derivatives 1-5 were obtained from the IC 50 values as per competitive inhibition (Cheng-Prusoff equation), in agreement with the inhibition patterns in this series of compounds and with experiments investigating the effect of increasings ubstrate concentrations (Table 1).…”

“…To investigate the inhibitory activity of the phenylboronic acid derivatives, full‐length KPC‐2 and KPC‐2 with a C‐terminal deletion were overexpressed and purified in a single chromatographic step to yield more than 150 mg of protein per liter of culture, with a purity degree higher than 99 %. Under our experimental conditions, the K m value for nitrocefin measured for full‐length KPC‐2 was determined as 36.0 μ m …”

“…Proteins were conveniently purified in a single step by using a Macro‐Prep High S resin and were eluted by using 50 m m sodium acetate pH 5.0 and a sodium chloride (NaCl) linear gradient from 100 to 500 m m . Purified proteins were dialyzed overnight in 50 m m sodium phosphate buffer pH 7.0 …”

Protective Cellular Mechanism of Estrogen Against Kidney Stone Formation: A Proteomics Approach and Functional Validation

“…Therefore, promotion of cell repairing/healing process is important for renoprotection and stone prevention. Several previous studies have demonstrated the effects of estrogen on cell migration and tissue healing that involved many signaling pathways, e.g., MAPK and PI3K pathways . In concordance, our proteomics data showed that mitogen‐activated protein kinase 1 (MAPK1) (spot #339) was significantly increased in the estrogen‐treated cells.…”

Poly I:C induces collective migration of HaCaT keratinocytes via IL-8

“…For example, TLR4 plays an essential role in early skin wound healing [7]. HMGB1, an endogenous ligand of TLR4, accelerates wound healing [8, 9], whereas a bacterial lipopolysaccharide, an exogenous ligand of TLR4, delayed cutaneous wound healing [10]. Activation of TLR9 by CpG oligodeoxynucleotides accelerates wound healing [11].…”