Review
Antimicrobial peptides and proteins in the innate defense of the airway surface

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Abstract

Recent studies have advanced our understanding of innate immune mechanisms that protect the airways and maintain a sterile lung. Multiple antimicrobial peptides and proteins have been identified in airway secretions and their roles are beginning to be established in animal models. Moreover, evidence for coupling between the innate and adaptive immune systems is beginning to emerge. The understanding of the innate airway defense system offers the opportunity for the development of novel therapeutic approaches.

Introduction

Throughout the day and night, our airways are exposed to bacteria by inhalation and aspiration. Yet, despite this, the airways are usually kept sterile. This protection results from an elaborate and redundant defense network that includes components of both the innate and acquired immune systems.

When bacteria enter the airway, they encounter the innate immune system (Fig. 1). Mucus acts as a physical barrier and binds organisms for subsequent removal via mucociliary clearance and cough [1]. Below the mucus lies a thin layer of airway surface liquid (ASL) containing antimicrobial factors that kill bacteria. In addition, roaming macrophages engulf and destroy bacteria. In so doing, they and the airway epithelia release cytokines, recruiting neutrophils and other circulating cells [2]. Surfactant protein A (SP-A) and SP-D, which arise from alveoli, bind to bacteria and fungi, further enhancing clearance by neutrophils and macrophages [3]. When organisms are not rapidly disposed of, they may activate receptors such as the Toll receptor on macrophages, dendritic cells and airway epithelia, thus priming the acquired immune system [4], [5].

Table 1 contrasts the innate immune system with the more widely appreciated acquired immune system. The evolutionarily ancient innate immune system does not require previous exposure to pathogens or immunologic memory although expression of some components increases during bacterial challenge. The antibacterial peptides and proteins of the innate immune system are relatively nonspecific and rapidly kill invading microbes. In contrast, B and T cells proliferate and fine-tune the specificity of their response after pathogen exposure; thus, unlike innate responses, adaptive responses are improved upon re-exposure. The antimicrobial factors in ASL are designed to control small numbers of bacteria whereas the adaptive immune system is tailored to handle large numbers of bacteria and established infections. However, the adaptive immune response can take days and often produces inflammatory side-effects that may damage the airways. Maintenance of healthy airways requires both systems. Here, we briefly review recent work on a key component of the innate defense system, airway antimicrobial peptides and proteins.

Section snippets

Concentration and location

ASL contains a rich diversity of antimicrobial proteins and peptides; Table 2 shows several. Submucosal gland serous cells produce the bulk of these factors, with airway epithelia and neutrophils contributing to the mixture. The antibacterial factors present in the airway include proteins, such as lysozyme and lactoferrin, and peptides, such as human β-defensin 1 (HBD-1), HBD-2, LL-37 (a cathelicidin), HNPs (human neutrophil peptides) and acidic peptides as well as other small molecules.

Antimicrobial factors in airway surface liquid are part of an integrated defense system

Although most studies of ASL antimicrobial factors have focused on their individual action, it is apparent that ASL factors function together and with other components of the innate and adaptive immune system. These integrated actions are likely to increase antimicrobial potency and provide mechanisms to recruit additional components of the immune system if initial innate defenses are inadequate. Empirical support for the importance of multiple antimicrobial factors comes from studies of nasal

In vivo studies of antimicrobial factors

Nearly all studies of ASL antimicrobial peptides have been done using in vitro assays. This, plus the plethora of factors in ASL, raises the question of which factors are important to airway defense in vivo. Presumably all are important but evidence to support this assumption is minimal. One way to study the importance of individual factors would be to generate mice with disruptions in the genes encoding various airway antimicrobial factors. We expect that reports of such experiments will soon

Abnormalities of antimicrobial killing in disease

A genetic disruption of the antimicrobial defense system has been proposed to account for chronic airway infections in cystic fibrosis (CF) [31], [32]. Airway infections begin early in the course of disease with many different organisms, and then with time P. aeruginosa and Staphylococcus aureus predominate. In CF, the loss of the CFTR (CF transmembrane conductance regulator) Cl– channel may cause a higher ASL salt concentration that reduces antimicrobial potency, thereby impairing the innate

Opportunities for new therapeutic approaches in the airways

The rapid emergence of bacterial strains resistant to conventional antibiotics has hastened the search for new antimicrobial agents that could be used in the airways and elsewhere. Antimicrobial peptides are promising candidates: they kill a broad spectrum of microbes, they kill rapidly, they are relatively nonimmunogenic and resistant bacteria are uncommon [38]. Potential therapeutic peptides could be based on the defensins, cathelicidin-derived peptides or other known antimicrobial peptides

Conclusions and future prospects

It has been almost 80 years since Alexander Fleming described the bactericidal activity of lysozyme in airway secretions [49]. The renewed interest in this area now poses several questions and presents several opportunities. We do not know all the components of ASL and how they work in concert. ASL is a complex soup; we need to know what the ‘meat and potatoes’ are and how the various ‘spices’ interact and enhance the mix. We must also understand how ASL components interact with epithelial,

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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