Surfactant proteins A (SP-A) and D (SP-D) are soluble innate immune molecules which maintain lung homeostasis through their dual roles as anti-infectious and immunomodulatory agents. SP-A and SP-D ...bind numerous viruses including influenza A virus, respiratory syncytial virus (RSV) and human immunodeficiency virus (HIV), enhancing their clearance from mucosal points of entry and modulating the inflammatory response. They also have diverse roles in mediating innate and adaptive cell functions and in clearing apoptotic cells, allergens and other noxious particles. Here, we review how the properties of these first line defense molecules modulate inflammatory responses, as well as host-mediated immunopathology in response to viral infections. Since SP-A and SP-D are known to offer protection from viral and other infections, if their levels are decreased in some disease states as they are in severe asthma and chronic obstructive pulmonary disease (COPD), this may confer an increased risk of viral infection and exacerbations of disease. Recombinant molecules of SP-A and SP-D could be useful in both blocking respiratory viral infection while also modulating the immune system to prevent excessive inflammatory responses seen in, for example, RSV or coronavirus disease 2019 (COVID-19). Recombinant SP-A and SP-D could have therapeutic potential in neutralizing both current and future strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus as well as modulating the inflammation-mediated pathology associated with COVID-19. A recombinant fragment of human (rfh)SP-D has recently been shown to neutralize SARS-CoV-2. Further work investigating the potential therapeutic role of SP-A and SP-D in COVID-19 and other infectious and inflammatory diseases is indicated.
Pulmonary surfactant (PS) is a lipid–protein complex that forms films reducing surface tension at the alveolar air–liquid interface. Surfactant protein C (SP‐C) plays a key role in rearranging the ...lipids at the PS surface layers during breathing. The N‐terminal segment of SP‐C, a lipopeptide of 35 amino acids, contains two palmitoylated cysteines, which affect the stability and structure of the molecule. The C‐terminal region comprises a transmembrane α‐helix that contains a ALLMG motif, supposedly analogous to a well‐studied dimerization motif in glycophorin A. Previous studies have demonstrated the potential interaction between SP‐C molecules using approaches such as Bimolecular Complementation assays or computational simulations. In this work, the oligomerization state of SP‐C in membrane systems has been studied using fluorescence spectroscopy techniques. We have performed self‐quenching and FRET assays to analyze dimerization of native palmitoylated SP‐C and a non‐palmitoylated recombinant version of SP‐C (rSP‐C) using fluorescently labeled versions of either protein reconstituted in different lipid systems mimicking pulmonary surfactant environments. Our results reveal that doubly palmitoylated native SP‐C remains primarily monomeric. In contrast, non‐palmitoylated recombinant SP‐C exhibits dimerization, potentiated at high concentrations, especially in membranes with lipid phase separation. Therefore, palmitoylation could play a crucial role in stabilizing the monomeric α‐helical conformation of SP‐C. Depalmitoylation, high protein densities as a consequence of membrane compartmentalization, and other factors may all lead to the formation of protein dimers and higher‐order oligomers, which could have functional implications under certain pathological conditions and contribute to membrane transformations associated with surfactant metabolism and alveolar homeostasis.
The amount of surfactant deposited in the lungs and its overall pulmonary distribution determine the therapeutic outcome of surfactant replacement therapy. Most of the currently available methods to ...determine the intrapulmonary distribution of surfactant are time-consuming and require surfactant labelling. Our aim was to assess the potential of Mass Spectrometry Imaging (MSI) as a label-free technique to qualitatively and quantitatively evaluate the distribution of surfactant to the premature lamb.
Twelve preterm lambs (gestational age 126-127d, term ~150d) were allocated in two experimental groups. Seven lambs were treated with an intratracheal bolus of the synthetic surfactant CHF5633 (200 mg/kg) and 5 lambs were managed with mechanical ventilation for 120 min, as controls. The right lung lobes of all lambs were gradually frozen while inflated to 20 cmH
O pressure for lung cryo-sections for MSI analysis. The intensity signals of SP-C analog and SP-B analog, the two synthetic peptides contained in the CHF5633 surfactant, were used to locate, map and quantify the intrapulmonary exogenous surfactant.
Surfactant treatment was associated with a significant improvement of the mean arterial oxygenation and lung compliance (p < 0.05). Nevertheless, the physiological response to surfactant treatment was not uniform across all animals. SP-C analog and SP-B analog were successfully imaged and quantified by means of MSI in the peripheral lungs of all surfactant-treated animals. The intensity of the signal was remarkably low in untreated lambs, corresponding to background noise. The signal intensity of SP-B analog in each surfactant-treated animal, which represents the surfactant distributed to the peripheral right lung, correlated well with the physiologic response as assessed by the area under the curves of the individual arterial partial oxygen pressure and dynamic lung compliance curves of the lambs.
Applying MSI, we were able to detect, locate and quantify the amount of exogenous surfactant distributed to the lower right lung of surfactant-treated lambs. The distribution pattern of SP-B analog correlated well with the pulmonary physiological outcomes of the animals. MSI is a valuable label-free technique which is able to simultaneously evaluate qualitative and quantitative drug distribution in the lung.
Problem
Preeclampsia (PE), a multifactorial disorder characterized by impaired placental development, elevated inflammatory response and dysregulated placental steroidogenesis. PE may be preventable ...if predicted early on.
Method of study
The study evaluated the potential of immunomodulatory collectins, surfactant protein A (SP‐A), surfactant protein D (SP‐D), and mannose binding lectin (MBL), to predict PE before the disease onset, in a prospective study cohort of healthy pregnant women (n = 922). In addition, a cross‐sectional study was conducted to determine the serum and placental profile of collectins in PE women after the disease onset (early‐onset PE EOPE, n = 33; late‐onset PE LOPE, n = 24); and controls n = 75. The serum profiles of estradiol (E2) and progesterone (P4) were evaluated to determine their correlation with collectins.
Results
In the prospective cohort, significantly decreased serum levels of SP‐A, SP‐D, P4/E2 ratio were observed in women who subsequently developed severe EOPE. Interestingly, after the disease onset, there was a significant increase in serum and placental levels of collectins in women with severe EOPE, whereas women with LOPE had significantly decreased levels of collectins. Serum P4/E2 ratio was significantly altered in severe EOPE and positively correlated with serum levels of SP‐A and SP‐D.
Conclusion
Collectins are differentially expressed in the serum during progression of PE. Decreased serum levels of SP‐A, SP‐D, P4/E2 ratio and increased E2 during 10‐20 weeks of gestation are novel plausible risk factors for early prediction of EOPE in Indian women.
Serum levels of SP‐A, SP‐D and P4/E2 ratio before and after the onset of severe early onset preeclampsia. Serum levels of SP‐A, SP‐D and P4/E2 ratio decreased significantly at 10‐20 weeks of gestation (prior to disease onset) with a potential predictive value in women with impending severe early onset preeclampsia (n=15) in a prospective cohort of 922 pregnant women. Cross‐sectional analysis with 12 cases and 30 controls showed significant increase in the levels of SP‐A, SP‐D and P4/E2 ratio after the onset of severe early onset preeclampsia.
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•Wettability modification of lignite surface by nonionic surfactant was studied by MD.•Hydrophilic groups of nonionic surfactant affect adsorption strength and hydrophobic ...alteration.•C12E7 is better than C12G2 in strengthening hydrophobic of lignite surface.
Abundant oxygen-containing functional groups make lignite high moisture content, which reduces the utilization efficiency of lignite. The decrease in hydrophilicity of lignite surface can be achieved by treating with surfactant. In the present work, two kinds of nonionic surfactants with different hydrophilic groups, n-dodecyl β-D-maltoside (C12G2) and dodecyl hepta glycol (C12E7), were selected to modify the wettability of lignite surface by molecular dynamics simulation. Because of the drastic differences in compositions and structure of their headgroups, different behaviors were observed. The adsorption results of simulation indicate that polyhydroxy surfactant, C12G2, adsorbs strongly on lignite surface as a comparison to the poly ether surfactant, C12E7. However, the extent of hydrophobicity of modified lignite surface by these surfactants is inconsistent with their adsorption capabilities. Compared to the raw lignite, the hydrophilicity of lignite significantly decreases by adsorption of C12E7, while the C12G2 makes the lignite even more hydrophilicity. The strong polar oxygen-containing functional groups of lignite surface are covered by ethers in C12E7 with weaker polarity, which weakens the interaction between water and lignite. The hydrophilicity of lignite adsorbed C12G2 is strengthened due to the increase in surface polarity by the introduction of polar hydroxyl groups. The results of simulations are in accord with the available experimental data.
CHF5633 (Chiesi Farmaceutici S.p.A., Parma, Italy) is the first fully synthetic surfactant enriched by peptide analogues of
human surfactant proteins. We planned to assess safety and tolerability of ...CHF5633 and explore preliminary efficacy.
Multicentre cohort study.
Forty infants from 27
to 33
weeks gestation with respiratory distress syndrome requiring fraction of inspired oxygen (FiO
) ≥0.35 were treated with a single dose of CHF5633 within 48 hours after birth. The first 20 received 100 mg/kg and the second 20 received 200 mg/kg.
Adverse events (AEs) and adverse drug reactions (ADRs) were monitored with complications of prematurity considered AEs if occurring after dosing. Systemic absorption and immunogenicity were assessed. Efficacy was assessed by change in FiO
after dosing and need for poractant-alfa rescue.
Rapid and sustained improvements in FiO
were observed in 39 (98%) infants. One responded neither to CHF5633 nor two poractant-alfa doses. A total of 79 AEs were experienced by 19 infants in the 100 mg/kg cohort and 53 AEs by 20 infants in the 200 mg/kg cohort. Most AEs were expected complications of prematurity. Two unrelated serious AEs occurred in the second cohort. One infant died of necrotising enterocolitis and another developed viral bronchiolitis after discharge. The single ADR was an episode of transient endotracheal tube obstruction following a 200 mg/kg dose. Neither systemic absorption, nor antibody development to either peptide was detected.
Both CHF5633 doses were well tolerated and showed promising clinical efficacy profile. These encouraging data provide a basis for ongoing randomised controlled trials.
ClinicalTrials.gov NCT01651637.
Foam has been applied in enhanced oil recovery (EOR) for more than sixty years. The surfactant-stabilized N2/CO2 foams are two of the most widely used foams in foam EOR processes, and numerous oil ...reservoirs could potentially benefit from them. This paper comprehensively reviews the development of these foams over the past decade. We focused on the promising surfactant formulas and their corresponding mechanisms under different reservoir conditions, especially harsh conditions. The most recent studies have shown that low interfacial tension foaming surfactants are efficient in fractured/tight reservoirs, while CO2-switchable surfactants are well suited to CO2 foam in carbonate reservoirs with high temperatures. Pure surfactants and mixed surfactants that combine anions and cations contain superior foam properties. The surfactant aggregates, such as vesicles and wormlike micelles, could distinctly enhance the foam stability. However, the adsorption of the mixed surfactants on reservoir rocks and the temperature sensitivity of the complex structures should be given particular consideration. The phase behaviors involved in foam EOR processes are vital and much more complicated than those in other EOR processes. Thus, a better knowledge of the phase behaviors could further improve foam EOR performance. The results of this paper provide clues to N2/CO2 foam EOR design and also promote the development of harsh reservoirs.
Pathogenic variants in surfactant proteins SP-B and SP-C cause surfactant deficiency and interstitial lung disease. Surfactant proteins are synthesized as precursors (proSP-B, proSP-C), trafficked, ...and processed via a vesicular-regulated secretion pathway; however, control of vesicular trafficking events is not fully understood. Through the Undiagnosed Diseases Network, we evaluated a child with interstitial lung disease suggestive of surfactant deficiency. Variants in known surfactant dysfunction disorder genes were not found in trio exome sequencing. Instead, a de novo heterozygous variant in
was identified in the Ras/Rab GTPases family nucleotide binding domain, p.Asp136His. Functional studies were performed in
by knocking the proband variant into the conserved position (Asp135) of the ortholog,
Genetic analysis demonstrated that
Asp135His is damaging, producing a strong dominant negative gene product.
Asp135His heterozygotes were also defective in endocytosis and early endosome (EE) fusion. Immunostaining studies of the proband's lung biopsy revealed that RAB5B and EE marker EEA1 were significantly reduced in alveolar type II cells and that mature SP-B and SP-C were significantly reduced, while proSP-B and proSP-C were normal. Furthermore, staining normal lung showed colocalization of RAB5B and EEA1 with proSP-B and proSP-C. These findings indicate that dominant negative-acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease, and that RAB5B and EEs normally function in the surfactant secretion pathway. Together, the data suggest a noncanonical function for RAB5B and identify
p.Asp136His as a genetic mechanism for a surfactant dysfunction disorder.
Surfactant proteins, SP-A and SP-D, are collagen-containing C-type (calcium dependent) lectins called collectins, which contribute significantly to surfactant homeostasis and pulmonary immunity. ...These highly versatile innate immune molecules are involved in a range of immune functions including viral neutralization, clearance of bacteria, fungi and apoptotic and necrotic cells, down regulation of allergic reaction and resolution of inflammation. Their basic structures include a triple-helical collagen region and a C-terminal homotrimeric lectin or carbohydrate recognition domain (CRD). The trimeric CRDs can recognize carbohydrate or charge patterns on microbes, allergens and dying cells, while the collagen region can interact with receptor molecules present on a variety of immune cells in order to initiate clearance mechanisms. Studies involving gene knock-out mice, murine models of lung hypersensitivity and infection, and functional characterization of cell surface receptors have revealed the diverse roles of SP-A and SP-D in the control of lung inflammation. A recently proposed model based on studies with the calreticulin-CD91 complex as a receptor for SP-A and SP-D has suggested an anti-inflammatory role for SP-A and SP-D in naïve lungs which would help minimise the potential damage that continual low level exposure to pathogens, allergens and apoptosis can cause. However, when the lungs are overwhelmed with exogenous insults, SP-A and SP-D can assume pro-inflammatory roles in order to complement pulmonary innate and adaptive immunity. This review is an update on the structural and functional aspects of SP-A and SP-D, with emphasis on their roles in controlling pulmonary infection, allergy and inflammation. We also try to put in perspective the controversial subject of the candidate receptor molecules for SP-A and SP-D.
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