Anionic poly(amino acid)s dissolve F-actin and DNA bundles, enhance DNase activity, and reduce the viscosity of cystic fibrosis sputum

Abstract

. Anionic poly(amino acid)s dissolve F-actin and DNA bundles, enhance DNase activity, and reduce the viscosity of cystic fibrosis sputum.

Mucin Overproduction in Chronic Inflammatory Lung Disease

“…These gel-forming mucins are primarily responsible for the rheological properties of airway mucus (2). However, in disease states such as CF and chronic bronchitis, polymeric DNA and filamentous actin, two products of leukocyte lysis, contribute greatly to, and are the principal determinants of, the viscoelastic properties of the purulent sputum that is associated with these diseases (3,4). The molecular weights of mucins range between 2×10 6 Da and 40×10 6 Da, and they are composed of 50% to 85% carbohydrate (5)(6)(7).…”

Neutrophil extracellular traps as the main source of eDNA

“…Previous studies of DNA, F-actin [43], alginate [44], and other anionic filaments present at sites of infection confirm the generality of these biophysical arguments and suggest strategies for design of cationic amphiphiles with reduced binding to linear polyelectrolytes without loss of targeting to bacterial surfaces [45]. Even strong inhibition of cationic antibacterial peptide activity by DNA, F-actin, Medical Studies/Studia Medyczne 2017; 33/2 or other natural negatively charged biopolymers was observed in vitro [1][2][3][4][5][6]; their interaction with NETs is much more complex within in vivo settings. Some reports suggest that DNA release from neutrophils represents an innate immune response to trap, maintain, and buffer the release of cationic defence molecules in exact time-space where the pathogens are trapped.…”

“…The statement that the presence of eDNA is crucial for the biofilm formation and structural integrity is additionally established by the reports demonstrating that the treatment with DNase 1 reduces the attachment of microbial cells to the surface, inhibits the biofilm development, and reduces the mass of mature biofilm [65], which is determined by the impairment of cell-to-cell adhesion and joining elements in microbial aggregates [66,67]. Importantly, the co-administration of antimicrobial agents with factors that have the ability to disassemble the biofilm polyelectrolyte network, including DNase 1, considerably improves their antibacterial efficiency [5,68]. As well as the reports indicating the vital role of eDNA in the biofilm structure, it was demonstrated that eDNA acts as an agent affecting the neutrophilmediated response and triggering the phagocytosis.…”

“…Nevertheless, under physiological settings, excess of biopolymers is eliminated during phagocytosis of cell fragments [1][2][3][4][5][6]. During the inflammation or infectious exposure, chemotactic migration of neutrophils towards infected/inflamed tissue results in accumulation of PE in the extracellular fluid both as the consequence of formation of neutrophil extracellular traps (NETs) and activity of neutrophil proteases.…”

“…Importantly, elevated eDNA and NET levels and their accumulation in biological fluids is a factor activating innate immune responses, which considerably affect the development of such diseases as asthma and chronic obstructive pulmonary disease [48], periodontitis [49], antineutrophil cytoplasmic antibody-associated vasculitis (AAV) [29], or cancerassociated thrombosis [50]. Quantitative analysis of the physical chemistry of polyelectrolytes has been useful for designing possible countermeasures to release endogenous antimicrobial peptides trapped in the polyelectrolyte bundles present in purulent fluids [5,45,[51][52][53][54][55][56]. Better penetration through this complex network might be achieved using a nanotechnology approach.…”