Wound repair and skin regeneration is a very complex orchestrated process that is generally composed of four phases: hemostasis, inflammation, proliferation, and remodeling. Each phase involves the activation of different cells and the production of various cytokines, chemokines, and other inflammatory mediators affecting the immune response. The microbial skin composition plays an important role in wound healing. Indeed, skin commensals are essential in the maintenance of the epidermal barrier function, regulation of the host immune response, and protection from invading pathogenic microorganisms. Chronic wounds are common and are considered a major public health problem due to their difficult-to-treat features and their frequent association with challenging chronic infections. These infections can be very tough to manage due to the ability of some bacteria to produce multicellular structures encapsulated into a matrix called biofilms. The bacterial species contained in the biofilm are often different, as is their capability to influence the healing of chronic wounds. Biofilms are, in fact, often tolerant and resistant to antibiotics and antiseptics, leading to the failure of treatment. For these reasons, biofilms impede appropriate treatment and, consequently, prolong the wound healing period. Hence, there is an urgent necessity to deepen the knowledge of the pathophysiology of delayed wound healing and to develop more effective therapeutic approaches able to restore tissue damage. This work covers the wound-healing process and the pathogenesis of chronic wounds infected by biofilm-forming pathogens. An overview of the strategies to counteract biofilm formation or to destroy existing biofilms is also provided.

In order to investigate whether products derived from the oxidation of sebum can be responsible for the induction of inflammatory processes, HaCaT keratinocytes were treated with peroxidated squalene. NF-κB activation, secretion, and expression of IL-6, as well as peroxisome proliferator-activated receptor alpha (PPARα) mRNA and protein levels, were measured at the end of the treatment and after 24 and 48 hours of recovery. Squalene peroxidation products were administered in amounts able to elicit significant hyperproliferation and to induce lipoxygenase (LOX) activity. The results showed an early activation of NF-κB followed by an increase in PPARα mRNA and protein levels. Moreover, squalene peroxides induced an initial upregulation of IL-6 production and secretion that was counteracted by PPARα activation, as suggested by the subsequent decrease of NF-κB nuclear translocation and IL-6 levels. Inflammatory processes play an important role in the development of acne vulgaris. In combination with our own previous findings, which indicated an association between LOX stimulation and increased percentage of proinflammatory lipids in acne as well as a correlation between increased cytokine levels in the infundibulum, pilosebaceous duct hyperkeratinization, and augmented sebogenesis, the present data further support the involvement of lipid peroxides, in particular squalene peroxides, in establishing an inflammatory process in acne.

One of the many functions of skin is to protect the organism against a wide range of pathogens. Antimicrobial peptides (AMPs) produced by the skin epithelium provide an effective chemical shield against microbial pathogens. However, whereas antibacterial/antifungal activities of AMPs have been extensively characterized, much less is known regarding their wound healing-modulatory properties. By using an in vitro re-epithelialisation assay employing special cell-culture inserts, we detected that a derivative of the frog-skin AMP esculentin-1a, named esculentin-1a(1-21)NH₂, significantly stimulates migration of immortalized human keratinocytes (HaCaT cells) over a wide range of peptide concentrations (0.025–4 μM), and this notably more efficiently than human cathelicidin (LL-37). This activity is preserved in primary human epidermal keratinocytes. By using appropriate inhibitors and an enzyme-linked immunosorbent assay we found that the peptide-induced cell migration involves activation of the epidermal growth factor receptor and STAT3 protein. These results suggest that esculentin-1a(1-21)NH₂ now deserves to be tested in standard wound healing assays as a novel candidate promoter of skin re-epithelialisation. The established ability of esculentin-1a(1-21)NH₂ to kill microbes without harming mammalian cells, namely its high anti-Pseudomonal activity, makes this AMP a particularly attractive candidate wound healing promoter, especially in the management of chronic, often Pseudomonas-infected, skin ulcers.