Effects of airway surface liquid pH on host defense in cystic fibrosis

Berkebile, Abigail R.; McCray, Paul B.

doi:10.1016/j.biocel.2014.02.009

Cited by 44 publications

(44 citation statements)

References 58 publications

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“…A particularly important case of human AMPs with activity that can be influenced by pH is that found in the airway surface liquid (ASL) of individuals with cystic fibrosis (CF) [165,166], which is a lethal genetic disorder characterized by viscous mucus and bacterial colonization of the airways [167]. In the mammalian respiratory system, the ASL represents a first line of pulmonary defense by forming the interface between the environment and the host organism and helping to protect against the action of inhaled and aspirated bacteria by producing a variety of antimicrobial molecules [168,169].…”

Section: An Overview Of Ph Dependent Peptides and Proteins With Anmentioning

confidence: 99%

“…In the mammalian respiratory system, the ASL represents a first line of pulmonary defense by forming the interface between the environment and the host organism and helping to protect against the action of inhaled and aspirated bacteria by producing a variety of antimicrobial molecules [168,169]. These ASL molecules include AMPs, such as LL-37, HNP-1, HBD-1 and lactoferrin, along with antimicrobial proteins, such as lysozyme, surfactant protein A and surfactant protein D [165,166]. Many of these antimicrobial molecules also contribute to the pulmonary innate immune system by adorning lattices of extracellular DNA, chromatin, enzymes and other proteins to form neutrophil extracellular traps (NETs).…”

Section: An Overview Of Ph Dependent Peptides and Proteins With Anmentioning

confidence: 99%

“…These roles include: the direct inhibition of bacterial growth, the prevention of microbial biofilm formation and the regulation of other AMPs and antimicrobial proteins, such as LL-37, HBD-2 and lysozyme [173,174,175,176]. However, in CF, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to reduced HCO 3 − secretion and produces an abnormally acidic pH in ASL [177,178], which studies on humans and animal models have suggested can negatively affect the efficacy of ASL antimicrobial molecules and predispose CF airways to microbial infection (Figure 3) [165,179]. For example, recent studies on a porcine CF model showed that the low pH of the ASL inhibited the activity of LL-37, lactoferrin and other AMPs when directed against S. aureus and P. aeruginosa [180,181], which are known, major CF pathogens [182,183].…”

Section: An Overview Of Ph Dependent Peptides and Proteins With Anmentioning

confidence: 99%

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pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

et al. 2016

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Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel delivery systems. Nonetheless, many pH dependent AMPs and antimicrobial proteins have yet to be fully characterized and these molecules, as a whole, represent an untapped source of novel biologically active agents that could aid fulfillment of the urgent need for alternatives to conventional antibiotics, helping to avert a return to the pre-antibiotic era.

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Section: An Overview Of Ph Dependent Peptides and Proteins With Anmentioning

confidence: 99%

Section: An Overview Of Ph Dependent Peptides and Proteins With Anmentioning

confidence: 99%

Section: An Overview Of Ph Dependent Peptides and Proteins With Anmentioning

confidence: 99%

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pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

et al. 2016

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“…ystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) (1). In the respiratory tract, CFTR dysfunction leads to a dehydrated and volume-depleted airway surface liquid (ASL) (2,3).…”

mentioning

confidence: 99%

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

Forde

Schutte

Reeves

et al. 2016

Antimicrob Agents Chemother

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There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial agents for the treatment of many conditions, including cystic fibrosis (CF). The challenging conditions of the CF patient lung require robust AMPs that are active in an environment of high proteolytic activity but that also have low cytotoxicity and immunogenicity. Previously, we developed prodrugs of AMPs that limited the cytotoxic effects of AMP treatment by rendering the antimicrobial activity dependent on the host enzyme neutrophil elastase (NE). However, cytotoxicity remained an issue. Here, we describe the further optimization of the AMP prodrug (pro-AMP) model for CF to produce pro-WMR, a peptide with greatly reduced cytotoxicity (50% inhibitory concentration against CFBE41o-cells, >300 M) compared to that of the previous group of pro-AMPs. The bactericidal activity of pro-WMR was increased in NE-rich bronchoalveolar lavage (BAL) fluid from CF patients (range, 8.4% ؎ 6.9% alone to 91.5% ؎ 5.8% with BAL fluid; P ‫؍‬ 0.0004), an activity differential greater than that of previous pro-AMPs. In a murine model of lung delivery, the pro-AMP modification reduced host toxicity, with pro-WMR being less toxic than the active peptide. Previously, host toxicity issues have hampered the clinical application of AMPs. However, the development of application-specific AMPs with modifications that minimize toxicity similar to those described here can significantly advance their potential use in patients. The combination of this prodrug strategy with a highly active AMP has the potential to produce new therapeutics for the challenging conditions of the CF patient lung.

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“…It belongs to the family of ATP-binding cassette trans-porters and functions as a cAMP-dependent chloride channel that facilitates Cl -/HCO 3 -exchange in exocrine epithelia [1] . It serves to maintain an alkaline pH and dilute fluid secretions [2] . Defects in CFTR lead to dehydrated secretions and hyperviscous mucus, causing a multisystem disease with major effects in the respiratory, gastrointestinal, and hepatobiliary tracts.…”

Section: Introductionmentioning

confidence: 99%

Steady-State Therapy with Azithromycin or Low-Dose Prednisolone in Paediatric Cystic Fibrosis Patients: Inflammatory Markers and Disease Progression

Shmarina

Pukhalsky²,

Avakian³

et al. 2017

Int Arch Allergy Immunol

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Background: Anti-inflammatory therapy is a logical approach to slowing the inevitable lung function deterioration in cystic fibrosis (CF) patients. This study's aim was to evaluate inflammatory markers and disease progression in paediatric CF patients chronically treated with azithromycin or low-dose prednisolone. Methods: The study included 204 patients with CF and 100 healthy controls; 102 CF patients were treated with basic therapy only (without anti-inflammatory treatment; WAT), and 102 individuals received basic therapy along with azithromycin (n = 59) or low-dose prednisolone (n = 43). The median duration of therapy was 24 months (range 12-82) with azithromycin and 31 months (range 12-180) with prednisolone. A cross-sectional analysis of plasma and sputum biomarkers was performed. Results: Compared with the healthy controls, the WAT group showed elevated IFN-γ, IL-10 (total), and TGFβ₁ concentrations, and decreased TNFα (total) and adrenocorticotropic hormone (ACTH) levels (all p < 0.05). Plasma TNFα (total) concentrations in azithromycin/prednisolone patients were significantly higher than those in WAT patients and similar to those of healthy children. In contrast, IL-10 (total) levels were significantly decreased in azithromycin/prednisolone-treated patients compared with WAT patients. Children from the azithromycin group demonstrated ACTH levels similar to those of healthy controls. Azithromycin-treated patients showed a significantly reduced rate of CF-related liver disease and a significantly increased incidence of glucose metabolism disturbances. Conclusions: Steady-state anti-inflammatory treatments may have a sustained immunomodulatory action at systemic and local levels in CF patients. Further investigations are needed to assess the effects of supportive azithromycin therapy on the hypothalamic-pituitary-adrenal axis and the incidence of non-pulmonary CF complications.

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Effects of airway surface liquid pH on host defense in cystic fibrosis

Cited by 44 publications

References 58 publications

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

Steady-State Therapy with Azithromycin or Low-Dose Prednisolone in Paediatric Cystic Fibrosis Patients: Inflammatory Markers and Disease Progression

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