Department of Cell Biology, Duke University School Of Medicine, Durham, North Carolina, USA
Address correspondence to: Jo Rae Wright, Department of Cell Biology, Box 3709, Duke University School Of Medicine, Durham, North Carolina 27710, USA. Phone: (919) 668-0460; Fax: (919) 684-8106; E-mail: email@example.com.
First published May 15, 2003 - More info
The lung is a uniquely vulnerable organ. Residing at the interface of the body and the environment, the lung is optimized for gas exchange, having a very thin, delicate epithelium, abundant blood flow, and a vast surface area. Inherent in this structure is an enormous immunological burden from pathogens, allergens, and pollutants resident in the 11,000 liters of air inhaled daily. Fortunately, protective immune mechanisms act locally in the lung to facilitate clearance of inhaled pathogens and to modulate inflammatory responses. These defensive mechanisms include both innate (nonantibody-mediated) and adaptive (antibody-mediated) systems. The purpose of this commentary is to review briefly the functions of one unique lung innate immune system, pulmonary surfactant, and to highlight the recent findings of Wu et al. (1) described in this issue of the JCI. Wu and colleagues report a new and intriguing innate immune function of surfactant: direct antimicrobial activity.
Pulmonary surfactant is a lipoprotein complex that is synthesized and secreted by the alveolar type II epithelial cell and the airway Clara cell into the thin liquid layer that lines the epithelium (reviewed in ref. 2). Once in the extracellular space, surfactant carries out two distinct functions. First, it reduces surface tension at the air-liquid interface of the lung, a function that requires an appropriate mix of surfactant lipids and the hydrophobic proteins, surfactant protein B (SP-B) and SP-C (3). Second, surfactant plays a role in host defense against infection and inflammation (4). Two of the surfactant proteins, SP-A and SP-D, are members of the collectin protein family (5, 6), which includes the liver-derived serum mannose binding lectin. Collectins have in common an N-terminal collagen-like region and a C-terminal lectin domain that binds carbohydrates in a calcium-dependent manner (Figure 1). The C-type lectin domains are arrayed with spatial orientation (7) that confers unique carbohydrate specificities, and their preferential binding sites are nonhost oligosaccharides, such as those found on bacterial and viral surfaces (8).
SP-A and SP-D are members of the collectin family of oligomeric proteins, which have collagen-like N-terminal regions and C-type carbohydrate recognition domains (CRDs). The CRDs bind carbohydrates such as those found on pathogen surfaces. SP-A consists of 6 structural units, which are assembled into a “flower bouquet” formation. SP-D consists of the tetrameric structural units assembled into an X-like structure. Figure adapted from an online article by N. Kawasaki that appears on Glycoforum(http://www.glycoforum.gr.jp/science/word/lectin/LEA06E.html).
The most well-defined function of the collectins is their ability to opsonize pathogens, including bacteria and viruses, and to facilitate phagocytosis by innate immune cells such as macrophages and monocytes. SP-A and SP-D also regulate production of inflammatory mediators (reviewed in ref. 4). Mice made deficient in SP-A or SP-D by homologous recombination have an enhanced susceptibility to infection and inflammation induced by intratracheal administration of pathogens, including Group B Streptococcus, Pseudomonas aeruginosa, respiratory syncytial virus, Haemophilus influenza, and inflammatory agents such as LPS (reviewed in ref. 9). Deficiencies in mannose-binding lectin have been characterized in humans and are associated with increased susceptibility to infection and autoimmune disease (10).
Data presented in the article by Wu and coworkers in this issue of the JCI (1) show convincingly that, in addition to facilitating pathogen uptake and killing by immune cells, SP-A and SP-D are directly antimicrobial, that is, they kill bacteria in the absence of immune effector cells (Figure 2). This conclusion is greatly strengthened by the multiple experimental approaches employed in the study. For example, Wu et al. demonstrate that exposure of Escherichia coli to SP-A and SP-D enhanced nuclear staining with propidium iodide, increased permeability to the antibiotic actinomycin D, and augmented release of proteins from the bacteria. Interestingly, inhibition of microbial growth was at least partly independent of collectin-mediated aggregation of bacteria and appears to involve damage to the bacterial cell membrane by the C-type lectin domains. Although SP-A and SP-D inhibited bacterial growth of a number of laboratory and clinical isolates, the factors that determine their specificity and the mechanism by which they increase membrane permeability are not known and will be important future avenues of investigation.
SP-A and SP-D enhance bacterial clearance and inhibit bacterial growth. SP-A and SP-D are oligomeric proteins synthesized by type II pulmonary epithelial cells and secreted in the liquid that covers the lung epithelium. Both SP-A and SP-D opsonize pathogens and enhance their phagocytosis by innate immune cells such as alveolar macrophages and neutrophils. In this issue of the JCI, Wu and coworkers provide compelling evidence that SP-A and SP-D also are directly bactericidal (1); they damage the bacterial cell membrane and inhibit bacterial growth. Thus, SP-A and SP-D enhance bacterial clearance via enhancing phagocytosis and via direct antimicrobial effects on bacteria. Images are not to scale.
Deficiencies of surfactant have been associated with a variety of lung diseases in both adults and infants. For example, infants born before their lungs have matured sufficiently suffer from respiratory distress syndrome due to the inability of their immature type II cells to synthesize adequate amounts of functional surfactant. Treatment with surfactant replacement therapies that include lipids and SP-B and/or SP-C have been highly efficacious in improving lung function in preterm newborns (11).
Surfactant inactivation and deficiencies have also been associated with a variety of adult lung diseases including pneumonia, asthma, and acute respiratory distress syndrome (ARDS) (reviewed in refs. 12, 13). Clinical trials have been undertaken for treatment of ARDS with surfactant replacement therapies containing either lipids or lipids plus SP-B and/or SP-C (14). However, these treatments have not been as effective in treating adult ARDS compared to infant respiratory distress syndrome. The new data presented by Wu and coworkers showing that SP-A and SP-D have direct bactericidal activity, in addition to their well-described opsonic activity and ability to regulate inflammatory mediator production, suggest that supplementation of the lipid-based therapies with SP-A and/or SP-D would further enhance their ability to treat infectious and inflammatory lung diseases (1). Importantly, recent studies have demonstrated that these proteins are expressed at extrapulmonary sites (15–17), raising the intriguing possibility that they may be efficacious for treatment of inflammatory and infectious diseases in other organs as well.
This work was supported by grants HL-30923, HL-68072, and HL-51134 from the NIH. The author thanks Soren Hansen for helpful suggestions.
See the related Commentary beginning on page 1589.
Conflict of interest: The author has declared that no conflict of interest exists.
Nonstandard abbreviations used: surfactant protein (SP); acute respiratory distress syndrome (ARDS).