Surfactant protein A (SP-A)-mediated bacterial clearance: SP-A and cystic fibrosis.

Abstract

Pulmonary Innate Defenses The constant challenge to the lung of inhaled microbes and noxious substances is largely kept in check by the innate and adaptive immune systems. Whereas the adaptive immune system is acquired and variable depending on previous challenges, the endogenous innate immune system is constitutively present and rapidly responds to inhaled particles. The principal function of innate immunity is to rapidly clear inhaled substances to prevent the establishment of an inflammatory process. Substances escaping the innate nasopharyngeal and tracheobronchial clearance mechanisms encounter a complex array of phagocytic and immunomodulatory cells and defensive molecules in the more distal lung. Defensins, lactoferrin, lysozyme, secretory leukoproteinase inhibitor (SLPI), secretory phospholipase A2, and cathelicidin LL-37 are recognized bacteriocidal molecules ( see Refs. 1–4 for review). Surfactant proteins A and D (SP-A and SP-D) are components of the innate defenses of the lung that act in concert with phagocytes to enhance clearance of invading microbes and other substances. SP-A and SP-D, produced and secreted by lung epithelial and tracheal gland cells, belong to the collectin family. Collectins share the same general protein structure of an amino terminal collagenous domain, a neck domain, and a carbohydrate recognition domain. Collectin genes have similar exon/intron junctions with the collagen domain encoded by several small exons and the carbohydrate recognition domain encoded by a single exon. Several collectin genes, including SP-A and SP-D, and at least one of the mannose binding lectin genes, are tightly linked on loci syntenic between the mouse and humans (5, 6). A considerable body of in vitro and in vivo studies support a role for SP-A and SP-D in pulmonary defense. Excellent recent reviews describe, in detail, functional and structural characteristics of the lung collectins ( see Refs. 7–16 for review). This review is limited mainly to studies demonstrating SP-A–mediated mechanisms of bacterial clearance with some comparisons to SP-D–mediated processes. SP-A–Mediated Bacterial Clearance Evidence generally supports at least four nonexclusive SP-A– mediated mechanisms. ( 1 ) SP-A binds and enhances uptake of bacteria by macrophages and neutrophils; ( 2 ) SP-A acts as an activation ligand, directly acting on macrophages or neutrophils to enhance phagocytosis; ( 3 ) SP-A enhances production of microbiocidal free radicals by cells; and ( 4 ) SP-A is a chemoattractant for phagocytes. Mechanisms and bacteria studied are summarized in Table 1.