Treatment with <scp>LL</scp>‐37 is safe and effective in enhancing healing of hard‐to‐heal venous leg ulcers: a randomized, placebo‐controlled clinical trial

Grönberg, Alvar; Mahlapuu, Margit; Ståhle, Mona; Whately‐Smith, Caroline; Rollman, Ola

doi:10.1111/wrr.12211

Cited by 150 publications

(115 citation statements)

References 39 publications

(78 reference statements)

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“…These results strongly suggest that decreased cathelicidin might contribute both to decreased bactericidal activity and increased levels of inflammation, resulting in greater tissue damage and higher bacterial loads. These findings, combined with our animal experiments and recent biochemical [47] and clinical studies [48, 49] involving cathelicidin, suggest a potential role for cathelicidin during acute illness as a novel therapeutic option for patients with leptospirosis.…”

Section: Discussionsupporting

confidence: 73%

Cathelicidin Insufficiency in Patients with Fatal Leptospirosis

et al. 2016

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Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10–50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms associated with case fatality. Whole blood transcriptional profiling of 16 hospitalized Brazilian patients with acute leptospirosis (13 survivors, 3 deceased) revealed fatal cases had lower expression of the antimicrobial peptide, cathelicidin, and chemokines, but more abundant pro-inflammatory cytokine receptors. In contrast, survivors generated strong adaptive immune signatures, including transcripts relevant to antigen presentation and immunoglobulin production. In an independent cohort (23 survivors, 22 deceased), fatal cases had higher bacterial loads (P = 0.0004) and lower anti-Leptospira antibody titers (P = 0.02) at the time of hospitalization, independent of the duration of illness. Low serum cathelicidin and RANTES levels during acute illness were independent risk factors for higher bacterial loads (P = 0.005) and death (P = 0.04), respectively. To investigate the mechanism of cathelicidin in patients surviving acute disease, we administered LL-37, the active peptide of cathelicidin, in a hamster model of lethal leptospirosis and found it significantly decreased bacterial loads and increased survival. Our findings indicate that the host immune response plays a central role in severe leptospirosis disease progression. While drawn from a limited study size, significant conclusions include that poor clinical outcomes are associated with high systemic bacterial loads, and a decreased antibody response. Furthermore, our data identified a key role for the antimicrobial peptide, cathelicidin, in mounting an effective bactericidal response against the pathogen, which represents a valuable new therapeutic approach for leptospirosis.

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Section: Discussionsupporting

confidence: 73%

Cathelicidin Insufficiency in Patients with Fatal Leptospirosis

et al. 2016

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“…Interestingly, LL-37 alone was sufficient to up-regulate some growth factors in NHEKs such as HBEGF. This observation is consistent with prior reports of accelerated reepithelialization by addition of LL-37 alone (41) and that LL-37 transactivates EGFR (42).…”

Section: Discussionsupporting

confidence: 83%

Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells

Adase

Borkowski

Zhang

et al. 2016

Journal of Biological Chemistry

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A critical function for skin is that when damaged it must simultaneously identify the nature of the injury, repair barrier function, and limit the intrusion of pathogenic organisms. These needs are carried out through the detection of damageassociated molecular patterns (DAMPs) and a response that includes secretion of cytokines, chemokines, growth factors, and antimicrobial peptides (AMPs). In this study, we analyzed how non-coding double-stranded RNA (dsRNAs) act as a DAMP in the skin and how the human cathelicidin AMP LL-37 might influence growth factor production in response to this DAMP. dsRNA alone significantly increased the expression of multiple growth factors in keratinocytes, endothelial cells, and fibroblasts. Furthermore, RNA sequencing transcriptome analysis found that multiple growth factors increase when cells are exposed to both LL-37 and dsRNA, a condition that mimics normal wounding. Quantitative PCR and/or ELISA validated that growth factors expressed by keratinocytes in these conditions included, but were not limited to, basic fibroblast growth factor (FGF2), heparin-binding EGF-like growth factor (HBEGF), vascular endothelial growth factor C (VEGFC), betacellulin (BTC), EGF, epiregulin (EREG), and other members of the transforming growth factor ␤ superfamily. These results identify a novel role for DAMPs and AMPs in the stimulation of repair and highlight the complex interactions involved in the wound environment.

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“…Many biofilms are accessible to topical treatment in the form of creams, aerosols, or direct application to sites that have been subjected to surgical debridement or drainage. Indeed this matches the known successful applications of peptides in clinical trials where evidence of efficacy via local treatment has been obtained [12,39]. However, peptides tend to be expensive drugs and although they are thought to engender very low resistance, there is always the possibility this will arise during therapy.…”

Section: Synergistic Combination Therapy To Fight Biofilm Infectionsmentioning

confidence: 84%

Design and Assessment of Anti-Biofilm Peptides: Steps Toward Clinical Application

Dostert¹,

Belanger²,

Hancock³

2018

J Innate Immun

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Highly antibiotic resistant, microbial communities, referred to as biofilms, cause various life-threatening infections in humans. At least two-thirds of all clinical infections are biofilm associated, and antibiotic therapy regularly fails to cure patients. Anti-biofilm peptides represent a promising approach to treat these infections by targeting biofilm-specific characteristics such as highly conserved regulatory mechanisms. They are being considered for clinical application and we discuss here key factors in discovery, design, and application, particularly the implementation of host-mimicking conditions, that are required to enable the successful advancement of potent anti-biofilm peptides from the bench to the clinic.

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Treatment with LL‐37 is safe and effective in enhancing healing of hard‐to‐heal venous leg ulcers: a randomized, placebo‐controlled clinical trial

Cited by 150 publications

References 39 publications

Cathelicidin Insufficiency in Patients with Fatal Leptospirosis

Cathelicidin Insufficiency in Patients with Fatal Leptospirosis

Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells

Design and Assessment of Anti-Biofilm Peptides: Steps Toward Clinical Application

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