Effect of Recombinant Surfactant Protein C–Based Surfactant on the Acute Respiratory Distress Syndrome

Spragg, Roger G.; Lewis, James F.; Walmrath, Hans‐Dieter; Johannigman, Jay A.; Bellingan, Geoff; Laterre, Pierre‐François; Witte, Michael C; Richards, Guy A.; Rippin, Gerd; Rathgeb, F.; Häfner, Dietrich; Taut, Friedemann; Seeger, Werner

doi:10.1056/nejmoa033181

Cited by 361 publications

(245 citation statements)

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“…Foremost, POPG is a natural constituent of human surfactant, and it has already been administered to adults and neonates in a variety of clinical settings as part of a more complex mixture that contains multiple surfactant components (25)(26)(27). In addition, POPG is a lowmolecular-weight lipid and as such, is extremely unlikely to induce any type of acquired immune response.…”

Section: Discussionmentioning

confidence: 99%

“…The data demonstrate that segregated pools of PG (i.e., not randomly mixed with other surfactant components) are necessary for effectively blocking engagement of TLR4-dependent processes. Indeed, it is likely that the random mixing of PG with other surfactant constituents has obscured its potency as both an anti-inflammatory and anti-RSV agent in previous studies (25)(26)(27). The cost and chemical stability of POPG also make it an attractive candidate for antiviral treatment in both developed and undeveloped countries.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection

Numata

Chu

Dakhama

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

161

244

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Respiratory syncytial virus (RSV) is the most common cause of hospitalization for respiratory tract infection in young children. It is also a significant cause of morbidity and mortality in elderly individuals and in persons with asthma and chronic obstructive pulmonary disease. Currently, no reliable vaccine or simple RSV antiviral therapy is available. Recently, we determined that the minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidylglycerol (POPG), could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. The phospholipid bound RSV with high affinity and inhibited viral attachment to HEp2 cells. POPG blocked viral plaque formation in vitro by 4 log units, and markedly suppressed the expansion of plaques from cells preinfected with the virus. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection, and abrogated IFN-γ (IFN-γ) production and the enhanced expression of surfactant protein D (SP-D). These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid.antiviral | innate immunity | respiratory epithelium R espiratory syncytial virus (RSV) is an important pathogen that infects 98% of children within the first 2 years of life, and also causes serious disease in elderly individuals and persons with chronic lung disease. In the 1980s, an estimated 100,000 children were hospitalized annually with RSV infection in the United States (1). Although RSV is commonly considered a pediatric disease, it is also highlighted as an opportunistic pathogen (2), with infections producing a mortality rate of 30-100% in immunosuppressed individuals (1). There is growing appreciation that RSV is an important pathogen in elderly and high-risk patients, and a cause of acute exacerbations of asthma (3, 4) and chronic obstructive pulmonary disease (COPD) (5). Over the period 1999-2003, RSV was responsible for hospitalization rates of 10.6% for pneumonia, 11.4% for COPD, 5.4% for congestive heart failure, and 7.2% for asthma (6).No vaccine is currently available for prevention of RSV infection. Several vaccine candidates have not only proved to be ineffective, but have also been shown to lead to vaccine-enhanced disease (7,8). Inhibitors directed against the RSV fusion protein (F protein) were abandoned partly because of the frequency of resistant mutations mapping to the F gene (9). A monoclonal antibody against F protein, Palivizumab, has restricted application and it is recommended for prophylactic use during the RSV season, for high-risk infants (1). Currently the onl...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection

Numata

Chu

Dakhama

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

161

244

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“…This rSP-C-containing surfactant has even been used in trials to treat patients with acute respiratory distress syndrome. Survival of these patients did not significantly improve upon receiving this surfactant, but the patients who received Venticute© displayed a greater improvement in gas exchange in the 24-hour treatment period than patients receiving standard therapy [149]. The favourable performance exhibited by recombinant SP-C variants harbouring phenylalanines instead of palmitoylated cysteines also seems to have a structural basis, since the resolution of the structure of a Phe-containing 28 recombinant SP-C by NMR reported no substantial differences when compared to the structure of wild-type native palmitoylated SP-C [150].…”

mentioning

confidence: 89%

Synthetic Pulmonary Surfactant Preparations: New Developments and Future Trends

Mingarro¹,

Lukovic²,

Vilar³

et al. 2008

CMC

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Pulmonary surfactant is a lipid-protein complex that coats the interior of the alveoli and enables the lungs to function properly. Upon its synthesis, lung surfactant adsorbs at the interface between the air and the hypophase, a capillary aqueous layer covering the alveoli. By lowering and modulating surface tension during breathing, lung surfactant reduces respiratory work of expansion, and stabilises alveoli against collapse during expiration.Pulmonary surfactant deficiency, or dysfunction, contributes to several respiratory pathologies, such as infant respiratory distress syndrome (IRDS) in premature neonates, and acute respiratory distress syndrome (ARDS) in children and adults. The main clinical exogenous surfactants currently in use to treat some of these pathologies are essentially organic extracts obtained from animal lungs. Although very efficient, natural surfactants bear serious defects: i) they could vary in composition from batch to batch; ii) their production involves relatively high costs, and sources are limited; and iii) they carry a potential risk of transmission of animal infectious agents and the possibility of immunological reaction. All these caveats justify the necessity for a highly controlled synthetic material.In the present review the efforts aimed at new surfactant development, including the modification of existing exogenous surfactants by adding molecules that can enhance their activity, and the progress achieved in the production of completely new preparations, are discussed. Pulmonary surfactant function and dysfunctionThe respiratory surface of lungs constitutes the largest area of the human body exposed to the environment. Efficient gas exchange requires a large enough surface to be continuously exposed to air while minimising the barriers for oxygen and carbon dioxide to diffuse between air and the blood compartment [1]. At the same time, a selection of combined defence mechanisms is required to help keep such an essentially exposed area sterile of potential pathogenic microorganisms. Pulmonary surfactant, a lipid-protein complex produced by the alveolar epithelium of lungs, has been optimised to coordinate two main activities through natural evolution. On the one hand, it stabilises the respiratory surface against physical forces, therefore minimising the work required to maintain the large respiratory surface open to air [2][3][4]. On the other hand, pulmonary surfactant contains elements responsible for establishing a primary innate antipathogenic barrier, essential to ensure an intrinsically low pathogen load in the absence of induced defence mechanisms [5]. Extensive research in the last few decades has revealed some of the molecular mechanisms involved in pulmonary surfactant action. However, the manner in which both the biophysical and defence activities are intermingled and coordinately modulated in the alveolar spaces is now only beginning to be envisioned.Pulmonary surfactant is composed of approximately 90% lipids and 8-10% proteins, although only around 5% ...

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“…5 Other groups have used combinations of pulmonary surfactants, including POPG, to treat RSV infection, acute lung injury (ALI) or ARDS with limited success. [6][7][8] Voelker suspects this is a result of using surfactant mixtures rather than pure POPG. "Our studies lead us to the conclusion that the reason these preparations have not been effective is because they are produced in a manner that causes random mixing of POPG with other lipids," he said.…”

Section: Taking Popg To the Lungmentioning

confidence: 99%

Giving RSV some POP(G)

Baas¹

2010

Science-Business eXchange

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A group at National Jewish Health has shown that a low-cost pulmonary surfactant called palmitoyl-oleoyl-phosphatidylglycerol, already known to attenuate respiratory syncytial virus-induced inflammatory responses, also inhibits binding of the virus to lung epithelial surfaces. 1 Although delivery and timing issues still need to be worked out, the surfactant's mechanism could offer a one-two punch to prevent or treat the infection.Respiratory syncytial virus (RSV) is a leading cause of hospitalization in children younger than six months. Infection progresses from a mild upper airway condition that in most cases goes undiagnosed to a more serious and less accessible lower airway episode. Major risk factors leading to serious RSV infection, which in turn can cause acute respiratory distress syndrome (ARDS), are preterm birth, congenital heart defects and chronic lung disease.The one approved drug for RSV is Synagis palivizumab from AstraZeneca plc's MedImmune LLC business unit. The anti-RSV antibody is indicated to prevent RSV in high-risk children. The average wholesale price is about $1,000 per shot, which is given monthly through the RSV season. That price tag has limited its use to premature infants and precluded its application in full-term infants and young children. 2 Indeed, the American Academy of Pediatrics' Committee on Infectious Disease revised its treatment guidelines last year, based on "issues of efficacy, cost, and evidence-based medicine, " which could decrease the number of premature infants considered candidates for Synagis.The most notable changes included the recommendations for infants of 32-35 weeks gestational age. Those infants that are three months old or less at the start of RSV season who also have at least one more risk factor are recommended to receive the prophylactic. The 2006 recommendations suggested that the infants be six months or less. 3 The group at National Jewish Health has been looking for lowcost alternatives. Their strategy is to increase the levels of pulmonary surfactant, a lipoprotein mixture secreted by the lung that plays a role in host innate immunity. The surfactant they have their sights set on, palmitoyl-oleoyl-phosphatidylglycerol (POPG), can be obtained from suppliers for about $400 per gram.In September 2009, Dennis Voelker and colleagues at National Jewish Health reported that POPG decreased toll-like receptor 4 (TLR4) activation and inflammatory responses to lipopolysaccharide in the lungs of mice. 4 Now, his team has shown that POPG directly binds RSV in vitro and reduces viral infection and lung pathology in vivo. 1In RSV-infected epithelial cell lines, POPG liposomes prevented both viral spread to neighboring cells and cell death. When the cells were treated with the liposomes prior to infection, RSV was unable to bind to the cell surface and RSV-induced proinflammatory cytokine production was reduced compared with what was seen using control phospholipids.In mice, intranasal delivery of POPG liposomes plus RSV resulted in significantly lower viral infec...

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Effect of Recombinant Surfactant Protein C–Based Surfactant on the Acute Respiratory Distress Syndrome

Cited by 361 publications

References 26 publications

Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection

Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection

Synthetic Pulmonary Surfactant Preparations: New Developments and Future Trends

Giving RSV some POP(G)

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