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 […]

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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 mannose 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) 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 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 phagocytosis 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. 1999. Pulmonary surfactant in health Immunol. Rev. 173:52–65. and human lung diseases: state of the art. Eur. 1. Wu, H., et al. 2003. Surfactant proteins A and D 7. Weis, W.I., and Drickamer, K. 1994. Trimeric Respir. J. 13:1455–1476. inhibit the growth of Gram-negative bacteria by structure of a C-type mannose-binding protein. 13. Gunther, A., et al. 2001. Surfactant alteration and increasing membrane permeability. J. Clin. Invest. Structure. 2:1227–1240. replacement in acute respiratory distress syn- 111:1589–1602. doi:10.1172/JCI200316889. 8. Crouch, E.C. 1998. Collectins and pulmonary drome. Respir. Res. 2:353–364. 2. Goerke, J. 1998. Pulmonary surfactant: functions host defense. Am. J. Respir. Cell Mol. Biol. 14. Jobe, A.H. 2000. Which surfactant for treatment of and molecular composition. Biochim. Biophys. 19:177–201. respiratory-distress syndrome. Lancet. 355:1380–1381. Acta. 1408:79–89. 9. Lawson, P.R., and Reid, K.B. 2000. The roles of 15. Madsen, J., et al. 2000. Localization of lung 3. Whitsett, J.A., Nogee, L.M., Weaver, T.E., and surfactant proteins A and D in innate immunity. surfactant protein D on mucosal surfaces in Horowitz, A.D. 1995. Human surfactant protein Immunol. Rev. 173:66–78. human tissue. J. Immunol. 164:5866–5870. B: structure, function, regulation, and genetic dis- 10. Jack, D.L., Klein, N.J., and Turner, M.W. 2001. 16. Akiyama, J., et al. 2002. Tissue distribution of sur- ease. Physiol. Rev. 75:749–757. Mannose-binding lectin: targeting the microbial factant proteins A and D in the mouse. J. His- 4. Wright, J.R. 1997. Immunomodulatory functions world for complement attack and opsonophago- tochem. Cytochem. 50:993–996. of surfactant. Physiol. Rev. 77:931–962. cytosis. Immunol. Rev. 180:86–99. 17. Dutton, J.M., et al. 1999. Surfactant protein A in 5. Crouch, E., and Wright, J.R. 2001. Surfactant pro- 11. Jacobs, H., et al. 1982. Premature lambs rescued rabbit sinus and middle ear mucosa. Ann. Otol. teins A and D and pulmonary host defense. Annu. from respiratory failure with natural surfactant: Rhinol. Laryngol. 108:915–924.

See the related article beginning on page 1547. in T lymphocytes, but not in monocytes, and thus is rapidly lost among The mitochondriotoxic domain of Vpr laboratory HIV-1 isolates. In contrast, Vpr is maintained in most HIV-1– determines HIV-1 virulence infected patients, indicating that this protein may be important for the in Catherine Brenner1 and Guido Kroemer2 vivo biology of HIV-1. In vitro, Vpr reduces the proliferation of CD4+ lym- 1Centre National de la Recherche Scientifique, Formation de Recherche en Évolution 2445, phocytes and of various other cell types Université de Versailles/St. Quentin,Versailles, France via a G2 cell cycle arrest. Moreover, Vpr 2Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8125, induces cell death through the intrin- Institut Gustave Roussy, Villejuif, France sic pathway of apoptosis, which J. Clin. Invest. 111:1455–1457 (2003). doi:10.1172/JCI200318609. involves mitochondrial membrane permeabilization (MMP), the release of cytochrome c from mitochondria, and Most patients infected with HIV-1 devel- T cells, as well as a low level of sponta- the cytochrome c–dependent activa- op AIDS unless they receive antiretrovi- neous apoptosis, correlating with a nor- tion of caspases (2, 3). ral medication. However, a small num- mal mitochondrial transmembrane A fraction of Vpr transfected into ber of HIV-infected individuals with potential (∆ψm) among circulating T cells can be found in the mitochondri- high viral titers remain disease free and cells. It has long been assumed that, as al compartment (2). When added to do not experience progressive immuno- an experimentum naturae, LTNPs might purified mitochondria, recombinant or suppression, even in the absence of ther- furnish valuable clues for the identifica- synthetic Vpr crosses the outer mem- apy. Such individuals are labeled long- tion of molecular determinants of brane through the voltage-dependent term nonprogressors (LTNPs) and are HIV-1 pathogenesis. A study by Badley anion channel. It then interacts with characterized by a series of laboratory and colleagues involving LTNPs, report- the adenine nucleotide translocator parameters that are usually compro- ed in this issue of the JCI (1), strongly (ANT) in the inner mitochondrial mised in HIV-1 carriers who ultimately suggests that viral protein R (Vpr) is a membrane to form a composite ion develop AIDS. In particular, LTNPs pos- major HIV-1 virulence factor. channel. This channel dissipates the + sess a high frequency of peripheral CD4 ∆ψm and thus favors MMP and subse- Vpr – a cytocidal protein quent apoptosis (3). The physical inter- Address correspondence to: Guido Kroemer, encoded by HIV-1 action between Vpr and ANT has been Centre National de la Recherche Scientifique, The HIV-1 genome encodes structural determined by coimmunoprecipita- Unité Mixte de Recherche 8125, Institut and enzymatic proteins common to all tion, electrophysiological measure- Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. retroviruses, but also some accessory ments, and surface plasmon resonance Phone: 33-1-42-11-60-46; proteins that are not always required (3). Vpr fails to kill ANT-deficient cells Fax: 33-1-42-11-60-47; E-mail: for the replication of HIV-1. One of (3), which suggests that the Vpr/ANT [email protected]. these accessory proteins, Vpr, is found interaction is central to the apoptosis- Conflict of interest: The authors have declared that no conflict of interest exists. in virions, HIV-1–infected cells, and in inducing properties of Vpr. Nonstandard abbreviations used: long-term the serum and cerebrospinal fluid of nonprogressive/nonprogressor (LTNP); HIV-1 carriers. Vpr is a small (96 amino Vpr is mutated in LTNPs mitochondrial transmembrane potential acids) soluble protein composed of In this issue of the JCI, Badley and col- (∆ψm); viral protein R (Vpr); mitochondrial membrane permeabilization (MMP); adenine three α-helical domains (Figure 1a). leagues (1) report that 80% of LTNPs nucleotide translocator (ANT). Vpr is dispensable for viral replication manifest a point mutation in Vpr

The Journal of Clinical Investigation | May 2003 | Volume 111 | Number 10 1455