Untapped Therapeutic Potential of Surfactant Proteins: Is There a Case for Recombinant SP-D Supplementation in Neonatal Lung Disease?

Clark, Howard

doi:10.1159/000297770

Cited by 12 publications

(12 citation statements)

References 114 publications

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“…Recombinant SP-A may have therapeutic potential, particularly as an adjunct treatment to current lipid surfactants alongside recombinant SP-D. These recombinant collectins could replace the deficient immunomodulatory host proteins SP-A and SP-D in the premature neonatal lung and prevent the development of neonatal chronic lung disease with associated respiratory and neurological complications (Clark, 2010). Recombinant SP-A and SP-D may also have potential as novel adjunctive synthetic anti-inflammatory and anti-infective agents in other disease settings including severe asthma and COPD (Clark, 2010, Mackay et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, comparative to full length recombinant SP-A molecules, trimeric rfhSP-A lacks the majority of the collagen domain and the N-terminal domain and thus has a lower propensity to self-aggregate, and has an increased solubility. The rfhSP-D of the closely related molecule SP-D is a well characterised molecule and has provided a wealth of information about the structure/function relationship of SP-D and mode of calcium-dependent ligand binding (Clark et al, 2016, Clark et al, 2005, Clark et al, 2003, Clark, 2010, Strong et al, 2002, Lin et al, 2010, Knudsen et al, 2007, Roona et al, 2012). Thus, this functional trimeric rfhSP-A may prove a useful reagent for research and has increased potential for development as a therapeutic as compared with full-length recombinant SP-A.…”

Section: Discussionmentioning

confidence: 99%

“…This fragment has been well characterised, structurally and functionally (Clark et al, 2016). Using this molecule, it has been demonstrated that the full collagen domain and N-terminal domain of SP-D are not essential for many of the natural functions of SP-D. For example, rfhSP-D has been shown to be effective in neutralising a range of pathogens including RSV (Clark, 2010, Hickling et al, 1999). rfhSP-D has also been shown to be effective in both decreasing allergic inflammation and 1,3 β-glucan mediated neutrophilic inflammation and decreasing the degree of emphysematous change in SP-D −/− mice (Fakih et al, 2015, Clark et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Novel expression of a functional trimeric fragment of human SP-A with efficacy in neutralisation of RSV

et al. 2017

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Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and hospitalisation of infants in developed countries. Surfactant protein A (SP-A) is an important innate immune molecule, localized in pulmonary surfactant. SP-A binds to carbohydrates on the surface of pathogens in a calcium-dependent manner to enable neutralisation, agglutination and clearance of pathogens including RSV.SP-A forms trimeric units and further oligomerises through interactions between its N-terminal domains. Whilst a recombinant trimeric fragment of the closely related molecule (surfactant protein D) has been shown to retain many of the native protein’s functions, the importance of the SP-A oligomeric structure in its interaction with RSV has not been determined.The aim of this study was to produce a functional trimeric recombinant fragment of human (rfh)SP-A, which lacks the N-terminal domain (and the capacity to oligomerise) and test its ability to neutralise RSV in an in vitro model of human bronchial epithelial infection.We used a novel expression tag derived from spider silk proteins (‘NT’) to produce rfhSP-A in Escherichia coli, which we found to be trimeric and to bind to mannan in a calcium-dependent manner. Trimeric rfhSP-A reduced infection levels of human bronchial epithelial (AALEB) cells by RSV by up to a mean (±SD) of 96.4 (±1.9) % at 5 μg/ml, which was significantly more effective than dimeric rfhSP-A (34.3 (±20.5) %) (p < 0.0001). Comparatively, native human SP-A reduced RSV infection by up to 38.5 (±28.4) %.For the first time we report the development of a functional trimeric rfhSP-A molecule which is highly efficacious in neutralising RSV, despite lacking the N-terminal domain and capacity to oligomerise.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel expression of a functional trimeric fragment of human SP-A with efficacy in neutralisation of RSV

et al. 2017

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“…Surfactant therapy has been used extensively and successfully in reducing mortality from respiratory distress syndrome of the newborn. 45 However, a significant proportion of infants born at less than 28 weeks' gestation develop neonatal chronic lung disease. Current surfactant therapies lack SP-D, yet animal models support a role for SP-D in reducing inflammation and infection in the lung, which suggests that supplementation of current surfactant therapies with recombinant forms of SP-D may help offset the risk of development of chronic lung disease.…”

Section: Discussionmentioning

confidence: 99%

Restoration of lung surfactant protein D by IL-6 protects against secondary pneumonia following hemorrhagic shock

Thacker

Moran

Lionakis

et al. 2014

Journal of Infection

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Summary Objectives To identify novel approaches to improve innate immunity in the lung following trauma complicated by hemorrhagic shock (T/HS) for prevention of nosocomial pneumonia. Methods We developed a rat model of T/HS followed by Pseudomonas aeruginosa (PA) pneumonia to assess the effect of alveolar epithelial cell (AEC) apoptosis, and its prevention by IL-6, on lung surfactant protein (SP)-D protein levels, lung bacterial burden, and survival from PA pneumonia, as well as to determine whether AEC apoptosis is a consequence of the unfolded protein response (UPR). Lung UPR transcriptome analysis was performed on rats subjected to sham, T/HS, and T/HS plus IL-6 protocols. Group comparisons were performed via Kaplan–Meier or ANOVA. Results T/HS decreased lung SP-D by 1.8-fold (p < 0.05), increased PA bacterial burden 9-fold (p < 0.05), and increased PA pneumonia mortality by 80% (p < 0.001). IL-6, when provided at resuscitation, normalized SP-D levels (p < 0.05), decreased PA bacterial burden by 4.8-fold (p < 0.05), and prevented all mortality from PA pneumonia (p < 0.001). The UPR transcriptome was significantly impacted by T/HS; IL-6 treatment normalized the T/HS-induced UPR transcriptome changes (p < 0.05). Conclusions Impaired innate lung defense occurs following T/HS and is mediated, in part, by reduction in SP-D protein levels, which, along with AEC apoptosis, may be mediated by the UPR, and prevented by use of IL-6 as a resuscitation adjuvant.

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“…Currently, pulmonary surfactant is regarded as standard treatment for children with acute respiratory failure [ 4 , 5 ]. Considering the impact of pulmonary surfactant on adult ARDS patients, a number of studies have explored the clinical benefits of administering pulmonary surfactant to adult patients with ARDS.…”

Section: Introductionmentioning

confidence: 99%

Effect of surfactant administration on outcomes of adult patients in acute respiratory distress syndrome: a meta-analysis of randomized controlled trials

Meng

Chang

et al. 2019

BMC Pulm Med

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IntroductionSurfactant is usually deficiency in adult acute respiratory distress syndrome(ARDS) patients and surfactant administration may be a useful therapy. The aim of this study was to perform a meta-analysis of the effect of surfactant administration on outcomes of adult patients with acute respiratory distress syndrome.MethodsPubMed, EMBASE, Medline, Cochrane database, Elsevier, Web of Science and http://clinicaltrials.gov were searched and investigated until December 2017. Randomized controlled trials(RCTs) comparing surfactant administration with general therapy in adult patients with ARDS were enrolled. The primary outcome was mortality (7–10-day, 28–30-day and 90–180-day). Secondary outcome included oxygenation (PaO2/FiO2 ratio). Demographic variables, surfactant administration, and outcomes were retrieved. Sensitivity analyses were used to evaluate the impact of study quality issues on the overall effect. Funnel plot inspection, Egger’s and Begger’s test were applied to investigate the publication bias. Internal validity was assessed with the risk of bias tool. Random errors were evaluated with trial sequential analysis(TSA). Quality levels were assessed by Grading of Recommendations Assessment, Development, and Evaluation methodology(GRADE).ResultsEleven RCTs with 3038 patients were identified. Surfactant administration could not improve mortality of adult patients [Risk ratio (RR) (95%CI)) = 1.02(0.93–1.12), p = 0.65]. Subgroup analysis revealed no difference of 7–10-day mortality [RR(95%CI)) = 0.89(0.54–1.49), p = 0.66], 28–30-day mortality[RR(95%CI) = 1.00(0.89–1.12), p = 0.98] and 90–180-day mortality [RR(95%CI) = 1.11(0.94–1.32), p = 0.22] between surfactant group and control group. The change of the PaO2/FiO2 ratio in adult ARDS patients had no difference [MD(95%CI) = 0.06(− 0.12–0.24), p = 0.5] after surfactant administration. Finally, TSA and GRADE indicated lack of firm evidence for a beneficial effect.ConclusionsSurfactant administration has not been shown to improve mortality and improve oxygenation for adult ARDS patients. Large rigorous randomized trials are needed to explore the effect of surfactant to adult ARDS patients.Electronic supplementary materialThe online version of this article (10.1186/s12890-018-0761-y) contains supplementary material, which is available to authorized users.

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Untapped Therapeutic Potential of Surfactant Proteins: Is There a Case for Recombinant SP-D Supplementation in Neonatal Lung Disease?

Cited by 12 publications

References 114 publications

Novel expression of a functional trimeric fragment of human SP-A with efficacy in neutralisation of RSV

Novel expression of a functional trimeric fragment of human SP-A with efficacy in neutralisation of RSV

Restoration of lung surfactant protein D by IL-6 protects against secondary pneumonia following hemorrhagic shock

Effect of surfactant administration on outcomes of adult patients in acute respiratory distress syndrome: a meta-analysis of randomized controlled trials

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