Scratching the surface: inroads to a better understanding of airway host defense.

Mammalian mucosal surfaces, including that of the respiratory tract, are truly remarkable from the perspective of host defense. Their life-sustaining physiologic roles dictate that these sites maintain intimate contact with an outside world teeming with a wide array of microbes. In the respiratory and digestive tract, exposure is exaggerated by expansive surface area, which facilitates gas exchange or nutrient absorption, respectively. Environmental exposure at these sites predicts a host vulnerability, as it provides an opportunity for microbes to establish invasive infections. Yet, given the countless encounters with microbes, there is an astonishingly low incidence of infection. Furthermore, inflammation as a defense mechanism is infrequently mobilized. This is probably advantageous, as inflammation at these sites would disrupt normal physiology. These simple observations suggest that efficient, highly vigilant, noninflammatory antimicrobial defenses, capable of dealing with a wide spectrum of microbes, have evolved to provide lifelong protection of these vital mucosal surfaces. Innate immunity (also termed nonclonal or natural immunity) encompasses a complex of first-line host defense elements (1). At mucosal surfaces the innate defense system employs two broad and overlapping strategies that are central to effective defense: minimizing microbial adherence and creating a hostile environment for potential pathogens. In the respiratory tract, examples of innate defenses include: ( 1 ) physical processes , such as induced turbulent flow of inspired air, coughing, clearance through beating of cilia and shedding of epithelial cells, ( 2 ) chemical barriers , such as mucus, nitric oxide, and various peptides and proteins, and ( 3 ) cellular processes , such as phagocytosis by resident macrophages (2–6). Through these mechanisms, innate immunity provides direct incapacitation and elimination of pathogens. Innate immunity also provides mechanisms to recognize microbial organisms as foreign. This recognition can lead to inducible responses, which can amplify and integrate host-defense pathways. Additionally, the innate host defense mechanisms interface with the acquired (also termed clonal or adaptive) immune responses mediated by lymphocytes (7, 8). However, in contrast to the lymphocyte-mediated immune system, where an effective response involves both gene rearrangements and clonal selection developed over a period of days, the innate system remains ever-ready or immediately inducible. Huttner and Bevins have recently proposed a working model of the host defense of mucosal surfaces in which elements of the innate host-defense system effectively deal with the vast majority of encounters with microbes and prevent infection (9). The model accommodates recent discoveries that defense of mammalian wet mucosal surfaces includes inducible and constitutive expression of antimicrobial peptides (10–14), inorganic molecules with antimicrobial activity (15, 16), and proteins that can directly inhibit microbial survival (17). These factors, highlighted in Figure 1, coupled with barrier properties and clearance mechanisms, constitute essential elements of innate mucosal immunity. In general, the antimicrobial factors are made in situ by surface and glandular epithelial cells, but in some cases they may also be derived from resident macrophages. Only when the local defenses are overwhelmed will the secondary lines of defense be called into action. The previously mentioned model suggests that inflammation and the acquired immune response as back-up systems are available to counter persistent or invasive challenges. Microorganisms may overwhelm local defenses if they have pathogenic attributes to evade defense mechanisms or if the challenge involves an exceptional number of microbes (Table 1). In addition, inadequate mucosal host-defense responses, for even routine microbial challenges, may result from genetic deficiencies, developmental immaturity, concurrent systemic disease, or environmental exposures (e.g., toxins). If the deficit in defense capacity is of limited duration, and if the host survives the infectious challenge, the mucosal defense system will return to baseline homeostasis. However, the consequence of long-term deficits would be persistent pathophysiology, which may include chronic inflammation and/or chronic mucosal infection. A key study that focused attention on local innate defense of the respiratory tract was published in 1996 by Smith and colleagues from the University of Iowa (18). This study investigated the mechanisms that underlie the clinical observations of local host defense defects in the respiratory mucosa of individuals with cystic fibrosis (CF). Their findings indicate that defective function of CF transmembrane conductance regulator protein (CFTR) leads to an alteration in airway surface liquid (ASL) composition, ( Received in original form March 24, 1999 )