The anti-inflammatory and antiviral properties of anionic pulmonary surfactant phospholipids.

The pulmonary surfactant system of the lung is a lipid and protein complex, which regulates the biophysical properties of the alveoli to prevent lung collapse and the innate immune system in the lung. Pulmonary surfactant is a lipoprotein complex consisting of 90% phospholipids and 10% protein, by weight. Two minor components of pulmonary surfactant phospholipids, phosphatidylglycerol (PG) and phosphatidylinositol (PI), exist at very high concentrations in the extracellular alveolar compartments. We have reported that one of the most dominant molecular species of PG, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and PI inhibit inflammatory responses induced by multiple toll-like receptors (TLR2/1, TLR3, TLR4, and TLR2/6) by interacting with subsets of multiprotein receptor components. These lipids also exert potent antiviral effects against RSV and influenza A, in vitro, by inhibiting virus binding to host cells. POPG and PI inhibit these viral infections in vivo, in multiple animal models. Especially noteworthy, these lipids markedly attenuate SARS-CoV-2 infection including its variants. These lipids are natural compounds that already exist in the lung and, thus, are less likely to cause adverse immune responses by hosts. Collectively, these data demonstrate that POPG and PI have strong potential as novel therapeutics for applications as anti-inflammatory compounds and preventatives, as treatments for broad ranges of RNA respiratory viruses.

Phosphatidylglycerol and surfactant: A potential treatment for COVID-19?

A hypothesis concerning the potential utility of surfactant supplementation for the treatment of critically ill patients with COVID-19 is proposed, along with a brief summary of the data in the literature supporting this idea. It is thought that surfactant, which is already approved by the Food and Drug Administration for intratracheal administration to treat neonatal respiratory distress syndrome in pre-term infants, could benefit COVID-19-infected individuals by: (1) restoring surfactant damaged by lung infection and/or decreased due to the virus-induced death of the type II pneumocytes that produce it and (2) reducing surface tension to decrease the work of breathing and limit pulmonary edema. In addition, a constituent of surfactant, phosphatidylglycerol, could mitigate COVID-19-induced lung pathology by: (3) decreasing excessive innate immune system stimulation via its inhibition of toll-like receptor-2 and -4 activation by microbial components and cellular proteins released by damaged cells, thereby limiting inflammation and the resultant pulmonary edema, and (4) possibly blocking spread of the viral infection to non-infected cells in the lung. Therefore, it is suggested that surfactant preparations containing phosphatidylglycerol be tested for their ability to improve lung function in critically ill patients with COVID-19.

Pulmonary surfactant lipids inhibit infections with the pandemic H1N1 influenza virus in several animal models.

The influenza A (H1N1)pdm09 outbreak in 2009 exemplified the problems accompanying the emergence of novel influenza A virus (IAV) strains and their unanticipated virulence in populations with no pre-existing immunity. Neuraminidase inhibitors (NAIs) are currently the drugs of choice for intervention against IAV outbreaks, but there are concerns that NAI-resistant viruses can transmit to high-risk populations. These issues highlight the need for new approaches that address the annual influenza burden. In this study, we examined whether palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI) effectively antagonize (H1N1)pdm09 infection. POPG and PI markedly suppressed cytopathic effects and attenuated viral gene expression in (H1N1)pdm09-infected Madin-Darby canine kidney cells. POPG and PI bound to (H1N1)pdm09 with high affinity and disrupted viral spread from infected to noninfected cells in tissue culture and also reduced (H1N1)pdm09 propagation by a factor of 102 after viral infection was established in vitro In a mouse infection model of (H1N1)pdm09, POPG and PI significantly reduced lung inflammation and viral burden. Of note, when mice were challenged with a typically lethal dose of 1000 plaque-forming units of (H1N1)pdm09, survival after 10 days was 100% (14 of 14 mice) with the POPG treatment compared with 0% (0 of 14 mice) without this treatment. POPG also significantly reduced inflammatory infiltrates and the viral burden induced by (H1N1)pdm09 infection in a ferret model. These findings indicate that anionic phospholipids potently and efficiently disrupt influenza infections in animal models.

Anionic 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) liposomes induce antigen-specific regulatory T cells and prevent atherosclerosis in mice.

Atherosclerosis is the predominant underlying pathology of many types of cardiovascular disease and is one of the leading causes of death worldwide. It is characterized by the retention of oxidized low-density lipoprotein (ox-LDL) in lipid-rich macrophages (foam cells) in the intima of arteries. Autoantigens derived from oxLDL can be used to vaccinate against atherosclerosis. However, a major challenge is the induction of antigen-specific Tregs in a safe and effective way. Here we report that liposomes containing the anionic phospholipid 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) induce Tregs that are specific for the liposomes' cargo. Mechanistically, we show a crucial role for the protein corona that forms on the liposomes in the circulation, as uptake of DSPG-liposomes by antigen-presenting cells is mediated via complement component 1q (C1q) and scavenger receptors (SRs). Vaccination of atherosclerotic mice on a western-type diet with DSPG-liposomes encapsulating an LDL-derived peptide antigen significantly reduced plaque formation by 50% and stabilized the plaques, and reduced serum cholesterol concentrations. These results indicate that DSPG-liposomes have potential as a delivery system in vaccination against atherosclerosis.

Soy Phosphatidylglycerol Reduces Inflammation in a Contact Irritant Ear Edema Mouse Model In Vivo.

We have previously shown that phosphatidylglycerol (PG) regulates the function of keratinocytes, the predominant cells that compose the epidermis, inhibiting the proliferation of rapidly dividing keratinocytes. In particular, soy PG, a PG mixture with a high proportion of polyunsaturated fatty acids, is efficacious at inhibiting these proliferating keratinocytes. Psoriasis is a skin disorder characterized by hyperproliferation of keratinocytes and inflammation. Data in the lung suggest that PG in pulmonary surfactant inhibits inflammation. To investigate the possibility of using PG containing polyunsaturated fatty acids for the treatment of psoriasis, we examined the effect of soy PG on inflammation induced by the application of 12-O-tetradecanoylphorbol 13-acetate (TPA), a contact irritant, to mouse ears in vivo. We monitored ear thickness and weight as a measure of ear edema, as well as CD45-positive immune cell infiltration. Our results indicate that soy PG when applied together with 1,25-dihydroxyvitamin D3 (vitamin D), an agent known to acutely disrupt the skin barrier, suppressed ear edema and inhibited the infiltration of CD45-positive immune cells. On the other hand, neither PG nor vitamin D alone was effective. The combination also decreased tumor necrosis factor-α (TNFα) levels. This result suggested the possibility that PG was not permeating the skin barrier efficiently. Therefore, in a further study we applied PG in a penetration-enhancing vehicle and found that it inhibited inflammation induced by the phorbol ester and decreased CD45-positive immune cell infiltration. Our results suggest the possibility of using soy PG as a topical treatment option for psoriasis.

Effect of exogenous pulmonary surfactants on mortality rate in neonatal respiratory distress syndrome: A network meta-analysis of randomized controlled trials.

BACKGROUND: The utilization of multiple natural and synthetic products in surfactant replacement therapies in treatment of neonatal respiratory distress syndrome (NRDS) prompted us to take a closer looks at these various therapeutic options and their efficacies. The purpose of our study was to evaluate the effects of six exogenous pulmonary surfactants (EPS) (Survanta, Alveofact, Infasurf, Curosurf, Surfaxin and Exosurf) on mortality rate in NRDS by a network meta-analysis. METHODS: An exhaustive search of electronic databases was performed in PubMed, Ovid, EBSCO, Springerlink, Wiley, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang and VIP databases (last updated search in October 2014) to retrieve randomized controlled trials (RCTs) relevant to our study topic. Published clinical trials were screened based on the following inclusion criteria: (1) study design: RCTs; (2) interventions: treatment with Survanta, Alveofact, Infasurf, Curosurf, Surfaxin or Exosurf for NRDS; (3) study subject: infants with NRDS confirmed by clinical diagnosis; (4) outcome: the mortality rate of infants with NRDS. Statistical analysis was performed using Stata 12.0 software (Stata Corporation, College Station, TX, USA) and Comprehensive Meta-analysis (CMA 2.0) software. RESULTS: From the 1840 studies initially retrieved through database searches, a total of 17 high quality RCTs were selected for this network meta-analysis. The selected studies included a combined total of 57,223 infants with NRDS treated with various EPS (Survanta, 27,017; Alveofact, 159; Infasurf, 20,377; Curosurf, 20,911; Surfaxin, 646; Exosurf, 1640). Network meta-analysis results showed that the mortality rates in NRDS infants treated with Alveofact, Infasurf, Curosurf, Surfaxin, Exosurf were not significantly different compared to Survanta (Alveofact: OR = 1.163, 95% CI = 0.645-2.099, P = 0.616; Infasurf: OR = 0.985, 95% CI = 0.777-1.248, P = 0.897; Curosurf: OR = 0.789, 95% CI = 0.619-1.007, P = 0.056; Surfaxin: OR = 0.728, 95% CI = 0.477-1.112, P = 0.142; Exosurf: OR = 0.960, 95% CI = 0.698-1.319, P = 0.799). Notably, the surface under the cumulative ranking curves (SUCRA) value in Surfaxin group was significantly higher than the other five groups (Surfaxin: 80.4%; Survanta: 37.0%; Alveofact: 24.4%; Infasurf: 40.0%; Curosurf: 73.9%; Exosurf: 44.2%), suggesting that infant mortality rate in Surfaxin group was the lowest among the six EPS groups. CONCLUSION: Our study demonstrated that Surfaxin could effectively reduce the mortality rate of infants with NRDS and may have a better efficacy in NRDS treatment, compared to Survanta, Alveofact, Infasurf, Curosurf and Exosurf.

Phosphatidylglycerol provides short-term prophylaxis against respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) causes respiratory tract infections in young children, and significant morbidity and mortality in the elderly, immunosuppressed, and immunocompromised patients and in patients with chronic lung diseases. Recently, we reported that the pulmonary surfactant phospholipid palmitoyl-oleoyl-phosphatidylglycerol (POPG) inhibited RSV infection in vitro and in vivo by blocking viral attachment to epithelial cells. Simultaneous application of POPG along with an RSV challenge to mice markedly attenuated infection and associated inflammatory responses. Based on these findings, we expanded our studies to determine whether POPG is effective for prophylaxis and postinfection treatment for RSV infection. In vitro application of POPG at concentrations of 0.2-1.0 mg/ml at 24 h after RSV infection of HEp-2 cells suppressed interleukin-8 production up to 80% and reduced viral plaque formation by 2-6 log units. In vivo, the turnover of POPG in mice is relatively rapid, making postinfection application impractical. Intranasal administration of POPG (0.8-3.0 mg), 45 min before RSV inoculation in mice reduced viral infection by 1 log unit, suppressed inflammatory cell appearance in the lung, and suppressed virus-elicited interferon-γ production. These findings demonstrate that POPG is effective for short-term protection of mice against subsequent RSV infection and that it has potential for application in humans.

Lucinactant for the prevention of respiratory distress syndrome in premature infants.

Respiratory distress syndrome (RDS) is the leading cause of neonatal morbidity and mortality in premature infants. It is caused by surfactant deficiency and lung immaturity. Lucinactant is a synthetic surfactant containing sinapultide, a bioengineered peptide mimic of surfactant-associated protein B. A meta-analysis of clinical trials demonstrates that lucinactant is as effective as animal-derived surfactants in preventing RDS in premature neonates, and in vitro studies suggest it is more resistant to oxidative and protein-induced inactivation. Its synthetic origin confers lower infection and inflammation risks as well other potential benefits, which may make lucinactant an advantageous alternative to its animal-derived counterparts, which are presently the standard treatment for RDS.

Drug updates and approvals: 2012 in review.

Each year, the FDA approves many pharmaceuticals and products designed to treat or improve a patient's condition. The following is a sampling of some of the most important drugs approved in 2012 that specifically apply to nurse practitioner practice.

Lucinactant for the treatment of respiratory distress syndrome in neonates.

Respiratory distress syndrome (RDS) is a leading cause of morbidity and mortality in premature neonates. This syndrome is caused by a lack of endogenous surfactant production in the lungs. Surfactant replacement was established as a safe and effective treatment in the 1990s and has become the standard of care for these infants. Surfactant products are either protein-free synthetic phospholipid compounds or animal-derived lung preparations. Currently, about 90,000 infants a year receive treatment with one of the commercially available animal-derived surfactants. Lucinactant (Surfaxin®) is a new synthetic surfactant with a pulmonary surfactant-associated protein B mimic that recently received FDA approval. The clinical trials that have been performed, although underpowered, may indicate that lucinactant is superior to phospholipid synthetic surfactant preparations and at least as effective as animal-derived surfactants in reducing morbidity and mortality from RDS. This review summarizes the current clinical knowledge about lucinactant.

Neonatal non-invasive respiratory support: physiological implications.

The introduction of assisted ventilation for neonatal pulmonary insufficiency has resulted in the successful treatment of many previously fatal diseases. During the past three decades, refinement of invasive mechanical ventilation techniques has dramatically improved survival of many high-risk neonates. However, as with many advances in medicine, while mortality has been reduced, morbidity has increased in the surviving high-risk neonate. In this regard, introduction of assisted ventilation has been associated with chronic lung injury, also known as bronchopulmonary dysplasia. This disease, unknown prior to the appearance of mechanical ventilation, has produced a population of patients characterized by ventilator or oxygen dependence with serious accompanying pulmonary and neurodevelopmental morbidity. The purpose of this article is to review non-invasive respiratory support methodologies to address the physiologic mechanisms by which these methods may prevent the pathophysiologic effects of invasive mechanical ventilation.

A pilot, randomized, controlled clinical trial of lucinactant, a peptide-containing synthetic surfactant, in infants with acute hypoxemic respiratory failure.

OBJECTIVE: Inhibition of surfactant function and abnormal surfactant synthesis lead to surfactant dysfunction in children with acute hypoxemic respiratory failure. We evaluated whether intratracheal lucinactant, a synthetic, peptide-containing surfactant, was safe and well-tolerated in infants with acute hypoxemic respiratory failure, and assessed its effects on clinical outcomes. METHODS AND MAIN RESULTS: Infants ≤ 2 yrs of age with acute hypoxemic respiratory failure were enrolled in a phase II, double-blind, multinational, placebo-controlled randomized trial across 36 pediatric intensive care units. Infants requiring mechanical ventilation with persistent hypoxemia meeting acute lung injury criteria were randomized to receive intratracheal lucinactant (175 mg/kg) or air placebo. One retreatment was allowed 12-24 hrs after initial dosing if hypoxemia persisted. Peri-dosing tolerability of intratracheal lucinactant and adverse experiences were assessed. Mechanical ventilation duration was analyzed using analysis of variance. The Cochran-Mantel-Haenszel test was used for categorical variables.We enrolled 165 infants (84 lucinactant; 81 placebo) with acute hypoxemic respiratory failure. There were no significant differences in baseline subject characteristics, with the exception of a lower positive end-expiratory pressure and higher tidal volume in placebo subjects. The incidence of transient peri-dosing bradycardia and desaturation was significantly higher in the lucinactant treatment group. There were no statistical differences between groups for other adverse events or mortality. Oxygenation improved in infants randomized to receive lucinactant as indicated by fewer second treatments (67% lucinactant vs. 81% placebo, p = .02) and a trend in improvement in partial pressure of oxygen in arterial blood to fraction of inspired oxygen from eligibility to 48 hrs after dose (p = .06). There was no significant reduction in duration of mechanical ventilation with lucinactant (geometric least square means: 4.0 days lucinactant vs. 4.5 days placebo; p = .254). In a subset of infants (n = 22), the duration of mechanical ventilation in children with acute lung injury (partial pressure of oxygen in arterial blood to fraction of inspired oxygen >200) was significantly shorter with lucinactant (least square means: 2.4 days lucinactant vs. 4.3 days placebo; p = .006). CONCLUSIONS: In mechanically ventilated infants with acute hypoxemic respiratory failure, treatment with intratracheal lucinactant appeared to be generally safe. An improvement in oxygenation and a significantly reduced requirement for retreatment suggests that lucinactant might improve lung function in infants with acute hypoxemic respiratory failure.

Surfactant lavage therapy for meconium aspiration syndrome: a systematic review and meta-analysis.

BACKGROUND: Lung lavage with diluted surfactant has emerged as an innovative treatment for meconium aspiration syndrome (MAS). However, the treatment effect has not yet been fully established. OBJECTIVE: To investigate the effects of surfactant lavage therapy for MAS by a systematic meta-analysis. METHODS: Relevant studies were identified by database searches in MEDLINE (from 1950), EMBASE (from 1980), and CENTRAL, up to June 2010, and by additional hand searches. Meta-analyses were separately conducted for randomized controlled trials (RCTs) and non-randomized controlled studies (NRSs). Risk of bias was assessed and clinical as well as statistical heterogeneities were also investigated in explaining the potential bias. RESULTS: Two RCTs (87 patients) and eight NRSs (178 patients) were identified. From the results of the meta-analysis of RCTs, surfactant lavage significantly decreased death or the need for extracorporeal membrane oxygenation (RR 0.34, 95% CI 0.11, 0.99). An interventional benefit was indicated for other outcomes, although it was not statistically significant based only on the two RCTs. Results from the analysis of outcomes from NRSs are consistent with those from RCTs and demonstrated a beneficial effect, which could be considered as supporting evidence. CONCLUSIONS: Lung lavage with diluted surfactant appeared to improve the clinical outcome in infants with MAS. Given that less than 100 infants were included in the two RCTs, the findings of this study may still be regarded as insufficient evidence. Further research will be needed to confirm the benefit as well as to refine the lavage technique.

Comparative effects of bronchoalveolar lavage with saline, surfactant, or perfluorocarbon in experimental meconium aspiration syndrome.

OBJECTIVE: Today, in meconium aspiration syndrome, treatment focuses on bronchoalveolar lavage, because it removes meconium and proinflammatory factors from airways. This technique might be more effective if different solutions were used such as saline solution, a protein-free surfactant, or a perfluorocarbon, because these would be less inhibited by meconium proteins. SETTING: Pulmonary physiology research unit, Cruces Hospital. DESIGN: Prospective, randomized study. SUBJECTS: We studied 24 lambs (<6 days) on mechanical ventilation for 180 mins. Catheters were placed and femoral and pulmonary arteries pressures registered (systemic and pulmonary arterial pressures). INTERVENTIONS: Lambs were instilled with 20% meconium (3-5 mL/Kg) and were randomly assigned to one of the following groups (n = 6): control: only continuous mechanical ventilation; saline bronchoalveolar lavage: bronchoalveolar lavage with 30 mL/kg of saline solution; dilute surfactant bronchoalveolar lavage: bronchoalveolar lavage with 32 mL/kg of diluted surfactant (lucinactant, 10 mg/mL); or perfluorocarbon bronchoalveolar lavage: bronchoalveolar lavage with 30 mL/kg of perfluorocarbon. MEASUREMENTS AND MAIN RESULTS: Blood gases, cardiovascular parameters, and pulmonary mechanics were assessed. Meconium instillation produced severe hypoxia, hypercapnia, acidosis, and pulmonary hypertension with impairment of pulmonary mechanics (p < .05). Lung lavage with dilute surfactant resulted in the resolution of pulmonary hypertension as well as better gas exchange and pulmonary mechanics than the control group (p < .05). Bronchoalveolar lavage with perfluorocarbon produced a transient improvement in gas exchange and ventilatory indices in comparison with control and saline bronchoalveolar lavage groups. CONCLUSIONS: In lambs with meconium aspiration syndrome, bronchoalveolar lavage with diluted lucinactant is an effective therapy producing significant improvements in gas exchange, pulmonary hypertension, and pulmonary mechanics. In addition, bronchoalveolar lavage with perfluorocarbon appears to confer some advantages over lavage with equal volumes of saline or no lavage.

Pulmonary distribution of lucinactant and poractant alfa and their peridosing hemodynamic effects in a preterm lamb model of respiratory distress syndrome.

Tracheal instillation of surfactant to premature newborns improves their survivability but may transiently obstruct airways resulting in undesirable acute effects on cerebral blood flow (CBF) and oxygenation. The acute peridosing hemodynamic effects of surfactant administration may be avoided by minimizing the volume of surfactant administered, but smaller surfactant volumes may also result in less even distribution of surfactant throughout the lung. These experiments were undertaken to compare responses to two surfactants with different dose volumes (porcine-derived poractant alfa, 2.5 mL/kg vs peptide-based synthetic lucinactant, 5.8 mL/kg) given to newly delivered lambs at 85% gestation. Both surfactants resulted in similar improvements in blood gas values, a doubling of dynamic compliance, increases in brain tissue oxygen tension, and stable blood pressure with no significant change in CBF. Distribution of surfactant throughout the lungs was more uniform with lucinactant than poractant alfa when assessed by labeled microspheres. We conclude that improvements in lung mechanics, gas exchange, and changes in CBF are comparable for a porcine-derived and peptide-containing synthetic surfactant, despite instilled volumes differing by 2-fold. Intrapulmonary distribution of surfactant is more uniform after a larger volume is instilled.