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Pulmonary Surfactant: a Front Line of Lung Host Defense Pulmonary surfactant: a front line of lung host defense Jo Rae Wright J Clin Invest. 2003;111(10):1453-1455. https://doi.org/10.1172/JCI18650. Commentary 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 and lung host defense 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 […] Find the latest version: https://jci.me/18650/pdf COMMENTARIES See the related article beginning on page 1589. SP-A and SP-D, are members of the collectin protein family (5, 6), which Pulmonary surfactant: includes the liver-derived serum man- nose binding lectin. Collectins have in a front line of lung host defense common an N-terminal collagen-like region and a C-terminal lectin do- Jo Rae Wright main that binds carbohydrates in a calcium-dependent manner (Figure Department of Cell Biology, Duke University School Of Medicine, 1). The C-type lectin domains are Durham, North Carolina, USA arrayed with spatial orientation (7) J. Clin. Invest. 111:1453–1455 (2003). doi:10.1172/JCI200318650. that confers unique carbohydrate specificities, and their preferential binding sites are nonhost oligosac- The lung is a uniquely vulnerable ed by the alveolar type II epithelial cell charides, such as those found on bac- organ. Residing at the interface of the and the airway Clara cell into the thin terial and viral surfaces (8). body and the environment, the lung liquid layer that lines the epithelium The most well-defined function of is optimized for gas exchange, having (reviewed in ref. 2). Once in the extra- the collectins is their ability to a very thin, delicate epithelium, cellular space, surfactant carries opsonize pathogens, including bacte- abundant blood flow, and a vast sur- out two distinct functions. First, it ria and viruses, and to facilitate face area. Inherent in this structure is reduces surface tension at the air- phagocytosis by innate immune cells an enormous immunological burden liquid interface of the lung, a func- such as macrophages and monocytes. from pathogens, allergens, and pollu- tion that requires an appropriate mix SP-A and SP-D also regulate produc- tants resident in the 11,000 liters of of surfactant lipids and the hydro- tion of inflammatory mediators air inhaled daily. Fortunately, protec- phobic proteins, surfactant protein B (reviewed in ref. 4). Mice made defi- tive immune mechanisms act locally (SP-B) and SP-C (3). Second, surfac- cient in SP-A or SP-D by homologous in the lung to facilitate clearance of tant plays a role in host defense recombination have an enhanced sus- inhaled pathogens and to modulate against infection and inflammation ceptibility to infection and inflam- inflammatory responses. These de- (4). Two of the surfactant proteins, mation induced by intratracheal fensive mechanisms include both innate (nonantibody-mediated) and adaptive (antibody-mediated) sys- tems. The purpose of this commen- tary 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 func- tion of surfactant: direct antimicro- bial activity. Pulmonary surfactant and lung host defense Pulmonary surfactant is a lipoprotein complex that is synthesized and secret- Address correspondence to: Jo Rae Wright, Department of Cell Biology, Box 3709, Duke University School Of Medicine, Figure 1 Durham, North Carolina 27710, USA. SP-A and SP-D are members of the collectin family of oligomeric proteins, which have colla- Phone: (919) 668-0460; Fax: (919) 684-8106; gen-like N-terminal regions and C-type carbohydrate recognition domains (CRDs). The CRDs E-mail: [email protected]. bind carbohydrates such as those found on pathogen surfaces. SP-A consists of 6 structur- Conflict of interest: The author has declared that no conflict of interest exists. al units, which are assembled into a “flower bouquet” formation. SP-D consists of the Nonstandard abbreviations used: surfactant tetrameric structural units assembled into an X-like structure. Figure adapted from an online protein (SP); acute respiratory distress article by N. Kawasaki that appears on Glycoforum (http://www.glycoforum.gr.jp/science/ syndrome (ARDS). word/lectin/LEA06E.html). The Journal of Clinical Investigation | May 2003 | Volume 111 | Number 10 1453 Figure 2 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 phagocy- tosis by innate immune cells such as alveolar macrophages and neutrophils. In this issue of the JCI, Wu and coworkers provide compelling evi- dence 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. administration of pathogens, includ- growth was at least partly independ- variety of adult lung diseases including ing Group B Streptococcus, Pseudo- ent of collectin-mediated aggregation pneumonia, asthma, and acute respira- monas aeruginosa, respiratory syncytial of bacteria and appears to involve tory distress syndrome (ARDS) virus, Haemophilus influenza, and damage to the bacterial cell mem- (reviewed in refs. 12, 13). Clinical trials inflammatory agents such as LPS brane by the C-type lectin domains. have been undertaken for treatment of (reviewed in ref. 9). Deficiencies in Although SP-A and SP-D inhibited ARDS with surfactant replacement mannose-binding lectin have been bacterial growth of a number of therapies containing either lipids or characterized in humans and are laboratory and clinical isolates, the lipids plus SP-B and/or SP-C (14). associated with increased suscepti- factors that determine their specifici- However, these treatments have not bility to infection and autoimmune ty and the mechanism by which they been as effective in treating adult disease (10). increase membrane permeability are ARDS compared to infant respiratory not known and will be important distress syndrome. The new data pre- Newly defined antibacterial future avenues of investigation. sented by Wu and coworkers showing functions of surfactant that SP-A and SP-D have direct bacte- Data presented in the article by Wu Future directions: surfactant ricidal activity, in addition to their well- and coworkers in this issue of the JCI therapy for infectious and described opsonic activity and ability (1) show convincingly that, in addi- inflammatory lung diseases? to regulate inflammatory mediator tion to facilitating pathogen uptake Deficiencies of surfactant have been production, suggest that supplemen- and killing by immune cells, SP-A associated with a variety of lung dis- tation of the lipid-based therapies with and SP-D are directly antimicrobial, eases in both adults and infants. For SP-A and/or SP-D would further that is, they kill bacteria in the example, infants born before their enhance their ability to treat infectious absence of immune effector cells (Fig- lungs have matured sufficiently suffer and inflammatory lung diseases (1). ure 2). This conclusion is greatly from respiratory distress syndrome Importantly, recent studies have strengthened by the multiple experi- due to the inability of their immature demonstrated that these proteins are mental approaches employed in the type II cells to synthesize adequate expressed at extrapulmonary sites study. For example, Wu et al. demon- amounts of functional surfactant. (15–17), raising the intriguing possi- strate that exposure of Escherichia coli Treatment with surfactant replace- bility that they may be efficacious for to SP-A and SP-D enhanced nuclear ment therapies that include lipids and treatment of inflammatory and infec- staining with propidium iodide, SP-B and/or SP-C have been highly tious diseases in other organs as well. increased permeability to the antibi- efficacious in improving lung function otic actinomycin D, and augmented in preterm newborns (11). Acknowledgments release of proteins from the bacteria. Surfactant inactivation and deficien- This work was supported by grants Interestingly, inhibition of microbial cies have also been associated with a HL-30923, HL-68072, and HL-51134 1454 The Journal of Clinical Investigation | May 2003 | Volume 111 | Number 10 from the NIH. The author thanks Rev. Physiol. 63:521–554. clinical and biophysical correlates. Pediatr. Res. 6. Crouch, E., Hartshorn, K., and Ofek, I. 2000. Col- 16:424–429. Soren Hansen for helpful suggestions. lectins and pulmonary innate immunity. 12. Griese, M.
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