The Role of Pulmonary Surfactant Phospholipids in Fibrotic Lung Diseases.

Diffuse parenchymal lung diseases (DPLD) or Interstitial lung diseases (ILD) are a heterogeneous group of lung conditions with common characteristics that can progress to fibrosis. Within this group of pneumonias, idiopathic pulmonary fibrosis (IPF) is considered the most common. This disease has no known cause, is devastating and has no cure. Chronic lesion of alveolar type II (ATII) cells represents a key mechanism for the development of IPF. ATII cells are specialized in the biosynthesis and secretion of pulmonary surfactant (PS), a lipid-protein complex that reduces surface tension and minimizes breathing effort. Some differences in PS composition have been reported between patients with idiopathic pulmonary disease and healthy individuals, especially regarding some specific proteins in the PS; however, few reports have been conducted on the lipid components. This review focuses on the mechanisms by which phospholipids (PLs) could be involved in the development of the fibroproliferative response.

Pulmonary surfactant and COVID-19: A new synthesis

Chapter 1: COVID-19 pathogenesis poses paradoxes difficult to explain with traditional physiology. For instance, since type II pneumocytes are considered the primary cellular target of SARS-CoV-2;as these produce pulmonary surfactant (PS), the possibility that insufficient PS plays a role in COVID-19 pathogenesis has been raised. However, the opposite of predicted high alveolar surface tension is found in many early COVID-19 patients: paradoxically normal lung volumes and high compliance occur, with profound hypoxemia. That 'COVID anomaly' was quickly rationalised by invoking traditional vascular mechanisms-mainly because of surprisingly preserved alveolar surface in early hypoxemic cases. However, that quick rejection of alveolar damage only occurred because the actual mechanism of gas exchange has long been presumed to be non-problematic, due to diffusion through the alveolar surface. On the contrary, we provide physical chemical evidence that gas exchange occurs by an process of expansion and contraction of the three-dimensional structures of PS and its associated proteins. This view explains anomalous observations from the level of cryo-TEM to whole individuals. It encompasses results from premature infants to the deepest diving seals. Once understood, the COVID anomaly dissolves and is straightforwardly explained as covert viral damage to the 3D structure of PS, with direct treatment implications. As a natural experiment, the SARS-CoV-2 virus itself has helped us to simplify and clarify not only the nature of dyspnea and its relationship to pulmonary compliance, but also the fine detail of the PS including such features as water channels which had heretofore been entirely unexpected.Copyright ©

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.

Possible Benefits of Reformulating Antiviral Drugs with Nanoemulsion System in the Treatment of Novel Coronavirus Infection

Background: An outbreak of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection or COVID 19 has caused serious threats to all around the world. Until an effective and safe vaccine for novel coronavirus is developed by scientists, current drug therapy should be optimized for the control and treatment of COVID 19. Objective(s): In this manuscript, we present a perspective on possible benefits of reformulating antiviral drug dosage form with nanoemulsion system against novel coronavirus infection. Method(s): Literature review has been done on COVID 19, treatment strategies, novel drug delivery sys-tems and the role of pulmonary surfactant in lung protection. Result(s): Nanoemulsion system and its components have certain biophysical properties which could in-crease the efficacy of drug therapy. Antiviral drugs, delivered through a nanoemulsion system contain-ing P-gp inhibitor (surfactant and co-solvent), can minimize the cellular resistance to drugs and would potentiate the antiviral action of drugs. Pulmonary Surfactant (PS) assisted antiviral drug delivery by nanoemulsion system could be another effective approach for the treatment of COVID 19. The use of functional excipients like Pulmonary Surfactant (PS) and Surfactant Proteins (SPs) in the formulation of the antiviral drug-loaded nanoemulsion system can improve the treatment of coronavirus infection. Conclusion(s): In our opinion, for synergizing antiviral action, lipid and protein portion of PS and their commercial analogs should be explored by pharmaceutical scientists to use them as a functional excipi-ent in the formulation of antiviral drug-loaded nanoemulsion system.Copyright © 2021 Bentham Science Publishers.

Administration of Exogenous Surfactant and Cytosolic Phospholipase A2alpha Inhibitors may Help COVID-19 Infected Patients with Chronic Diseases

Background: Coronavirus-19 (COVID-19) pandemic is a worldwide public health problem causing 347,070 deaths from December 25, 2019, till May 25, 2020. Phospholipids are structural components of mammalian cytoskeleton and cell membranes. Phosphatidylglycerol is an anionic lipid found in mammalian membranes in low amounts (1-2%) of the total phospholipids. Also, phosphatidylglycerol suppresses viral attachment to the plasma membrane and subsequent replication in lung cells. Phosphatidylglycerol depletion caused by over expression of cytosolic phos-pholipase A2alpha induces lipid accumulation in lung alveoli and promotes acute respiratory distress syndrome (ARDS). An exogenous-surfactant replacement has been successfully achieved in ARDS and improved oxygenation and lung mechanics. Inhibition of cytosolic phospholipase A2alpha impairs an early step of COVID-19 replication. Aim(s): The present study was carried out to explain the correlation between the administration of exogenous artificial surfactant as well as cytosolic phospholipase A2alpha inhibitors to improve oxygenation and lung mechanics and inhibit COVID-19 replication. Method(s): Database research was carried out on Medline, Embase, Cochrane Library, country-spe-cific journals, and following-up WHO reports published between December 25, 2019-May 25, 2020. Result(s): Till 25 May 2020, coronavirus cases were 5,307,298, with 347,070 deathsand 2,314,849 recovered cases. According to the WHO reports, most COVID-19 deaths seen are in people who suffered from other chronic diseases characterized by phospholipidosis and phosphatidylglycerol deficiency, including hypertension, liver, heart, and lung diseases and diabetes. Phospholipases A2 (PLA2) catalyze the cleavage of fatty acids esterified at the sn-2 position of glycerophospholipids leading to enhanced inflammation and lung damage. Also, cytosolic phospholipase A2alpha inhibitors may reduce the accumulation of viral proteins and RNA. In addition, administration of exogenous phospholipid surfactant may help COVID-19 infected patients with ARDS to remove inflammatory mediators. Conclusion(s): The present study showed a relation between phosphatidylglycerol deficiency in COVID-19 infected patients with ARDS and/or chronic diseases and their mortality. These findings also showed an important approach for the prevention and treatment of COVID-19 infections by using cytosolic phospholipase A2alpha inhibitors and exogenous administration of a specific phos-pholipid surfactant.Copyright © 2021 Bentham Science Publishers.

Induction of systemic, mucosal, and cellular immunity against SARS-CoV-2 in mice vaccinated by trans-airway with a S1 protein combined with a pulmonary surfactant-derived adjuvant SF-10.

Background: There is a need for vaccines that can induce effective systemic, respiratory mucosal, and cellular immunity to control the COVID-19 pandemic. We reported previously that a synthetic mucosal adjuvant SF-10 derived from human pulmonary surfactant works as an efficient antigen delivery vehicle to antigen presenting cells in the respiratory and gastrointestinal tracts and promotes induction of influenza virus antigen-specific serum IgG, mucosal IgA, and cellular immunity. Methods: The aim of the present study was to determine the effectiveness of a new administration route of trans-airway (TA) vaccine comprising recombinant SARS-CoV-2 spike protein 1 (S1) combined with SF-10 (S1-SF-10 vaccine) on systemic, local, and cellular immunity in mice, compared with intramuscular injection (IM) of S1 with a potent adjuvant AddaS03™ (S1-AddaS03™ vaccine). Results: S1-SF-10-TA vaccine induced S1-specific IgG and IgA in serum and lung mucosae. These IgG and IgA induced by S1-SF-10-TA showed significant protective immunity in a receptor binding inhibition test of S1 and angiotensin converting enzyme 2, a receptor of SARS-CoV-2, which were more potent and faster achievement than S1-AddaS03™-IM. Enzyme-linked immunospot assay showed high numbers of S1-specific IgA and IgG secreting cells (ASCs) and S1-responsive IFN-γ, IL-4, IL-17A cytokine secreting cells (CSCs) in the spleen and lungs. S1-AddaS03™-IM induced IgG ASCs and IL-4 CSCs in spleen higher than S1-SF-10-TA, but the numbers of ASCs and CSCs in lungs were low and hardly detected. Conclusions: Based on the need for effective systemic, respiratory, and cellular immunity, the S1-SF-10-TA vaccine seems promising mucosal vaccine against respiratory infection of SARS-CoV-2.

Correlation between serum surfactant protein-D level with respiratory compliance and acute respiratory distress syndrome in critically ill COVID-19 Patients: A retrospective observational study.

Background: Acute respiratory distress syndrome (ARDS) is one of the manifestations of severe coronavirus disease 2019 (COVID-19) with low respiratory compliance and poor oxygenation as main characteristics and mortality rate of 50%-94%. Surfactants, including surfactant protein D (SP-D), have a role in maintaining respiratory compliance. This study aimed to analyze the relationship between serum SP-D levels with respiratory compliance and ARDS in patients with critically ill COVID-19 pneumonia. Methods: This study was a cross-sectional study. Subjects were adult reverse transcription-polymerase chain reaction-confirmed COVID-19 patients who had ARDS treated with invasive mechanical ventilation. All data were obtained from medical records. Statistical analysis was done using Spearman test, Mann-Whitney test, and receiver operating characteristic curve. Results: Serum level of SP-D was significantly correlated with static respiratory compliance (P = 0.009; correlation coefficient [rs] = 0.467). Serum SP-D levels correlated with ARDS severity (P < 0.001). SP-D levels had a very strong diagnostic value for ARDS severity, with an optimal cutoff value of 44.24 ng/mL (sensitivity 92.3%; specificity 94.1%). ARDS severity also correlated significantly with respiratory compliance (P = 0.005; correlation coefficient 0.496). Conclusion: Higher serum SP-D levels were associated with lower respiratory compliance, ARDS severity, and may be utilized diagnostically to identify patients with severe ARDS.

Pulmonary Surfactant Proteins are Inhibited by IgA Autoantibodies in Severe COVID-19.

RATIONALE: Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome with fatal outcomes. Evidence suggests that dysregulated immune responses, including autoimmunity, are key pathogenic factors. OBJECTIVES: To assess whether IgA autoantibodies target lung-specific proteins and contribute to disease severity. METHODS: We collected 147 blood, 9 lung tissue, and 36 bronchoalveolar lavage fluid samples from three tertiary hospitals in Switzerland and one in Germany. Severe COVID-19 was defined by the need to administer oxygen. We investigated the presence of IgA autoantibodies and their effects on pulmonary surfactant in COVID-19 using the following methods: immunofluorescence on tissue samples, immunoprecipitations followed by mass spectrometry on bronchoalveolar lavage fluid samples, enzyme-linked immunosorbent assays on blood samples, and surface tension measurements with medical surfactant. MEASUREMENTS AND MAIN RESULTS: IgA autoantibodies targeting pulmonary surfactant proteins B and C were elevated in patients with severe COVID-19, but not in patients with influenza or bacterial pneumonia. Notably, pulmonary surfactant failed to reduce surface tension after incubation with either plasma or purified IgA from patients with severe COVID-19. CONCLUSIONS: Our data suggest that patients with severe COVID-19 harbor IgA against pulmonary surfactant proteins B and C and that these antibodies block the function of lung surfactant, potentially contributing to alveolar collapse and poor oxygenation. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Molecular Pathogenesis of Fibrosis, Thrombosis and Surfactant Dysfunction in the Lungs of Severe COVID-19 Patients.

The global scope and scale of the SARS-CoV-2 pandemic led to huge amounts of important data from clinical observations and experimental analyses being collected, in particular, regarding the long-term impact of COVID-19 on lung tissue. Visible changes in lung tissue mainly relate to the destruction of the alveolar architecture, dense cellularity, and pulmonary fibrosis with myofibroblast proliferation and collagen deposition. These changes are the result of infection, mainly with virus variants from the first pandemic waves (Alpha to Delta). In addition, proper regulation of immune responses to pathogenic viral stimuli is critical for the control of and recovery from tissue/organ damage, including in the lungs. We can distinguish three main processes in the lungs during SARS-CoV-2 infection: damage or deficiency of the pulmonary surfactant, coagulation processes, and fibrosis. Understanding the molecular basis of these processes is extremely important in the context of elucidating all pathologies occurring after virus entry. In the present review, data on the abovementioned three biochemical processes that lead to pathological changes are gathered together and discussed. Systematization of the knowledge is necessary to explore the three key pathways in lung tissue after SARS-CoV-2 virus infection as a result of a prolonged and intense inflammatory process in the context of pulmonary fibrosis, hemostatic disorders, and disturbances in the structure and/or metabolism of the surfactant. Despite the fact that the new Omicron variant does not affect the lungs as much as the previous variants, we cannot ignore the fact that other new mutations and emerging variants will not cause serious damage to the lung tissue. In the future, this review will be helpful to stratify the risk of serious complications in patients, to improve COVID-19 treatment outcomes, and to select those who may develop complications before clinical manifestation.

Pulmonary Surfactant: A Unique Biomaterial with Life-saving Therapeutic Applications.

Pulmonary surfactant is a complex lipoprotein mixture secreted into the alveolar lumen by type 2 pneumocytes, which is composed by tens of different lipids (approximately 90% of its entire mass) and surfactant proteins (approximately 10% of the mass). It is crucially involved in maintaining lung homeostasis by reducing the values of alveolar liquid surface tension close to zero at end-expiration, thereby avoiding the alveolar collapse, and assembling a chemical and physical barrier against inhaled pathogens. A deficient amount of surfactant or its functional inactivation is directly linked to a wide range of lung pathologies, including the neonatal respiratory distress syndrome. This paper reviews the main biophysical concepts of surfactant activity and its inactivation mechanisms, and describes the past, present and future roles of surfactant replacement therapy, focusing on the exogenous surfactant preparations marketed worldwide and new formulations under development. The closing section describes the pulmonary surfactant in the context of drug delivery. Thanks to its peculiar composition, biocompatibility, and alveolar spreading capability, the surfactant may work not only as a shuttle to the branched anatomy of the lung for other drugs but also as a modulator for their release, leading to innovative therapeutic avenues for the treatment of several respiratory diseases.

Elucidating the enhanced binding affinity of a double mutant SP-D with trimannose on the influenza A virus using molecular dynamics.

Surfactant protein D (SP-D) is an essential component of the human pulmonary surfactant system, which is crucial in the innate immune response against glycan-containing pathogens, including Influenza A viruses (IAV) and SARS-CoV-2. Previous studies have shown that wild-type (WT) SP-D can bind IAV but exhibits poor antiviral activities. However, a double mutant (DM) SP-D consisting of two point mutations (Asp325Ala and Arg343Val) inhibits IAV more potently. Presently, the structural mechanisms behind the point mutations' effects on SP-D's binding affinity with viral surface glycans are not fully understood. Here we use microsecond-scale, full-atomistic molecular dynamics (MD) simulations to understand the molecular mechanism of mutation-induced SP-D's higher antiviral activity. We find that the Asp325Ala mutation promotes a trimannose conformational change to a more stable state. Arg343Val increases the binding with trimannose by increasing the hydrogen bonding interaction with Glu333. Free energy perturbation (FEP) binding free energy calculations indicate that the Arg343Val mutation contributes more to the increase of SP-D's binding affinity with trimannose than Asp325Ala. This study provides a molecular-level exploration of how the two mutations increase SP-D binding affinity with trimannose, which is vital for further developing preventative strategies for related diseases.

Non-Cellular Layers of the Respiratory Tract: Protection against Pathogens and Target for Drug Delivery.

Epithelial barriers separate the human body from the environment to maintain homeostasis. Compared to the skin and gastrointestinal tract, the respiratory barrier is the thinnest and least protective. The properties of the epithelial cells (height, number of layers, intercellular junctions) and non-cellular layers, mucus in the conducting airways and surfactant in the respiratory parts determine the permeability of the barrier. The review focuses on the non-cellular layers and describes the architecture of the mucus and surfactant followed by interaction with gases and pathogens. While the penetration of gases into the respiratory tract is mainly determined by their hydrophobicity, pathogens use different mechanisms to invade the respiratory tract. Often, the combination of mucus adhesion and subsequent permeation of the mucus mesh is used. Similar mechanisms are also employed to improve drug delivery across the respiratory barrier. Depending on the payload and target region, various mucus-targeting delivery systems have been developed. It appears that the mucus-targeting strategy has to be selected according to the planned application.

Insights Gained Into the Treatment of COVID19 by Pulmonary Surfactant and Its Components.

Pulmonary surfactant constitutes an important barrier that pathogens must cross to gain access to the rest of the organism via the respiratory surface. The presence of pulmonary surfactant prevents the dissemination of pathogens, modulates immune responses, and optimizes lung biophysical activity. Thus, the application of pulmonary surfactant for the treatment of respiratory diseases provides an effective strategy. Currently, several clinical trials are investigating the use of surfactant preparations to treat patients with coronavirus disease 2019 (COVID-19). Some factors have been considered in the application of pulmonary surfactant for the treatment COVID-19, such as mechanical ventilation strategy, timing of treatment, dose delivered, method of delivery, and preparation utilized. This review supplements this list with two additional factors: accurate measurement of surfactants in patients and proper selection of pulmonary surfactant components. This review provides a reference for ongoing exogenous surfactant trials involving patients with COVID-19 and provides insight for the development of surfactant preparations for the treatment of viral respiratory infections.

Anti-inflammatory and anti-viral actions of anionic pulmonary surfactant phospholipids.

Pulmonary surfactant is a mixture of lipids and proteins, consisting of 90% phospholipid, and 10% protein by weight, found predominantly in pulmonary alveoli of vertebrate lungs. Two minor components of pulmonary surfactant phospholipids, phosphatidylglycerol (PG) and phosphatidylinositol (PI), are present within the alveoli at very high concentrations, and exert anti-inflammatory effects by regulating multiple Toll like receptors (TLR2/1, TLR4, and TLR2/6) by antagonizing cognate ligand-dependent activation. POPG also attenuates LPS-induced lung injury in vivo. In addition, these lipids bind directly to RSV and influenza A viruses (IAVs) and block interaction between host cells and virions, and thereby prevent viral replication in vitro. POPG and PI also inhibit RSV and IAV infection in vivo, in mice and ferrets. The lipids markedly inhibit SARS-CoV-2 infection in vitro. These findings suggest that both POPG and PI have strong potential to be applied as both prophylaxis and post-infection treatments for problematic respiratory viral infections.

Mechanisms of the Effects of Short-Term Inhalations of Xe and O2 Gas Mixture in the Rehabilitation of Post-COVID Ventilation Failure.

The article presents a theoretical rationale and a clinical case of relief of post-COVID ventilation failure by inhalation of Xe and O2 gas mixture. Pneumonitis of coronavirus etiology transforms saturated phospholipids of surfactant into a solid-ordered phase, which disrupts surface tension, alveolar pneumatization, and alveolar-capillary gas exchange. Using molecular modeling (B3LYP/lanl2dz; GAUSSIAN09), we demonstrated that Xe atom due to the van der Waals dispersion interaction increases the distance between the phospholipid acyl chains providing a phase transition from the solid-ordered to liquid phase and restored the surface-active monolayer surfactant film. A clinical case confirmed that short-term inhalations of the Xe and O2 gas mixture relieved manifestations of ventilation insufficiency and increased SpO2 and pneumatization of the terminal parts of the lungs.

Surfactant-based therapy against COVID-19: A review

The coronavirus disease 2019 (COVID-19) has led to serious health and economic damage to all over the world, and it still remains unstoppable. The SARS-CoV-2, by using its S-glycoprotein, binds with an angiotensin-converting enzyme 2 re-ceptor, mostly present in alveolar epithelial type II cells. Eventually pulmonary surfactant depletion occurs. The pulmonary surfactant is necessary for maintaining the natural immunity as well as the surface tension reduction within the lung alveoli during the ex-piration. Its insufficiency results in the reduction of blood oxyge-nation, poor pulmonary regeneration, lung fibrosis, and finally the respiratory system collapses. Exogenous surfactants have pre-viously shown great promise in the treatment of infant respiratory distress syndrome, and they may also aid in the healing of dam-aged alveolar cells and the prevention of respiratory failure. Sur-factant based therapy has been advised for the prevention of COVID-19, and the trials have begun around the world. Further-more, greater research on the timing, dose, and the distribution of surfactant to the COVID-19 patients is required before this tech-nique can be implemented in clinical practice.

Plasma Phospholipids: A Promising Simple Biochemical Parameter to Evaluate COVID-19 Infection Severity.

BACKGROUND: Coronavirus-19 (COVID-19) pandemic is a worldwide public health problem that has been known in China since December 25, 2019. Phospholipids are structural components of the mammalian cytoskeleton and cell membranes. They suppress viral attachment to the plasma membrane and subsequent replication in lung cells. In the virus-infected lung, phospholipids are highly prone to oxidation by reactive oxygen species, leading to the production of oxidized phospholipids (OxPLs). OBJECTIVE: This study was carried out to explain the correlation between the level of plasma phospholipids in patients with COVID-19 infection and the levels of cytokine storms to assess the severity of the disease. METHODS: Plasma samples from 34 enrolled patients with mild, moderate, and severe COVID-19 infection were collected. Complete blood count (CBC), plasma levels of D-dimer, ferritin, C-reactive protein (CRP), cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), phospholipids, secretory phospholipase A2 (sPLA2)α2, and cytokine storms were estimated, and lung computed tomography (CT) imaging was detected. RESULTS: The CBC picture showed the presence of leukopenia, lymphopenia, and eosinopenia in patients with COVID-19 infection. Furthermore, a significant increase was found in plasma levels of D-dimer, CRP, ferritin, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-13 as well as sPLA2α2 activity compared to normal persons. However, plasma levels of phospholipids decreased in patients with moderate and severe COVID-19 infection, as well as significantly decreased in levels of triacylglycerols and HDL-C in plasma from patients with severe infection only, compared to normal persons. Furthermore, a lung CT scan showed the presence of inflammation in a patient with mild, moderate, and severe COVID-19 infection. CONCLUSIONS: This study shows that there is a correlation between plasma phospholipid depletion and elevated cytokine storm in patients with COVID-19 infection. Depletion of plasma phospholipid levels in patients with COVID-19 infection is due to oxidative stress, induction of cytokine storm, and systemic inflammatory response after endothelial cell damage promote coagulation. According to current knowledge, patients with COVID-19 infection may need to administer surfactant replacement therapy and sPLA2 inhibitors to treat respiratory distress syndrome, which helps them to maintain the interconnected surfactant structures.

Pulmonary surfactant as a versatile biomaterial to fight COVID-19.

The COVID-19 pandemic has wielded an enormous pressure on global health care systems, economics and politics. Ongoing vaccination campaigns effectively attenuate viral spreading, leading to a reduction of infected individuals, hospitalizations and mortality. Nevertheless, the development of safe and effective vaccines as well as their global deployment is time-consuming and challenging. In addition, such preventive measures have no effect on already infected individuals and can show reduced efficacy against SARS-CoV-2 variants that escape vaccine-induced host immune responses. Therefore, it is crucial to continue the development of specific COVID-19 targeting therapeutics, including small molecular drugs, antibodies and nucleic acids. However, despite clear advantages of local drug delivery to the lung, inhalation therapy of such antivirals remains difficult. This review aims to highlight the potential of pulmonary surfactant (PS) in the treatment of COVID-19. Since SARS-CoV-2 infection can progress to COVID-19-related acute respiratory distress syndrome (CARDS), which is associated with PS deficiency and inflammation, replacement therapy with exogenous surfactant can be considered to counter lung dysfunction. In addition, due to its surface-active properties and membrane-interacting potential, PS can be repurposed to enhance drug spreading along the respiratory epithelium and to promote intracellular drug delivery. By merging these beneficial features, PS can be regarded as a versatile biomaterial to combat respiratory infections, in particular COVID-19.

Potential Therapeutic Applications of Pulmonary Surfactant Lipids in the Host Defence Against Respiratory Viral Infections.

Pulmonary surfactant is a complex and highly surface-active material. It covers the alveolar epithelium and consists of 90% lipids and 10% proteins. Pulmonary surfactant lipids together with pulmonary surfactant proteins facilitate breathing by reducing surface tension of the air-water interface within the lungs, thereby preventing alveolar collapse and the mechanical work required to breathe. Moreover, pulmonary surfactant lipids, such as phosphatidylglycerol and phosphatidylinositol, and pulmonary surfactant proteins, such as surfactant protein A and D, participate in the pulmonary host defense and modify immune responses. Emerging data have shown that pulmonary surfactant lipids modulate the inflammatory response and antiviral effects in some respiratory viral infections, and pulmonary surfactant lipids have shown promise for therapeutic applications in some respiratory viral infections. Here, we briefly review the composition, antiviral properties, and potential therapeutic applications of pulmonary surfactant lipids in respiratory viral infections.

Deceiving SARS-CoV-2 molecular-tropism clues - A combinational contemporary strategy.

Several attempts to control the dreadfulness of SARS-CoV-2 are still underway. Based on the literature evidences we have speculated a prospective contemporary remedy, which was categorized into Specificity, Remedy, and a Conveyor. In which, pros and cons were discussed and inferred the possible alternatives. (a) Specificity: Implicit to express the ACE2 receptors in conveyor cells to deceive SARS-CoV-2 frompreponetargets. (b) Remedy: As depletion of pulmonary surfactants causes strong acute respiratory distress syndrome, we propose an entity of a cost-effective artificialsurfactantsystem as a remedy to pulmonary complications. (c) Conveyor: We propose red blood cells (RBCs) as a conveyor with embedded artificial surfactant and protruding ACE2 receptors for the target-specific delivery. Overall we postulate focused insights by employing a combinational contemporary strategy to steer towards a prospective direction on combating SARS-CoV-2.