Alveolar Type II Cells and Pulmonary Surfactant in COVID-19 Era

In this review, we discuss the role of pulmonary surfactant in the host defense against respiratory pathogens, including novel coronavirus SARS-CoV-2. In the lower respiratory system, the virus uses angiotensin-converting enzyme 2 (ACE2) receptor in conjunction with serine protease TMPRSS2, expressed by alveolar type II (ATII) cells as one of the SARS-CoV-2 target cells, to enter. ATII cells are the main source of surfactant. After their infection and the resulting damage, the consequences may be severe and may include injury to the alveolar-capillary barrier, lung edema, inflammation, ineffective gas exchange, impaired lung mechanics and reduced oxygenation, which resembles acute respiratory distress syndrome (ARDS) of other etiology. The aim of this review is to highlight the key role of ATII cells and reduced surfactant in the pathogenesis of the respiratory form of COVID-19 and to emphasize the rational basis for exogenous surfactant therapy in COVID-19 ARDS patients.

To B or not to B. The rationale for quantifying B-lines in paediatric lung diseases.

The evaluation of the lung by ultrasound is an adjunct tool to the clinical assessment. Among different hallmarks at lung ultrasound, B-lines are well known artifacts which are not correlated to identifiable structures but can be used as an instrument for pathological classification. Multiple B-lines are the sonographic sign of lung interstitial syndrome with a direct correlation between the number of B-lines and the severity of the interstitial involvement of lung disease. In neonatology and paediatrics, the quantitative assessment of B-lines is questionable as opposed to in adult medical care. Counting B-lines is an attempt to enrich the clinical assessment and clinical information, and not simply arrive at a dichotomous answer. A semiquantitative or quantitative B-lines assessment was shown to correlate with fluid overload and demonstrated prognostic implications in specific neonatal and paediatric conditions. In neonatology, the count of B-lines is used to predict the need for admission in neonatal intensive care unit and the need for exogenous surfactant treatment. In paediatrics, the B-lines count has the role of quantifying hypervolemia in infants and children receiving dialysis. B-lines as predictors of length of stay in the paediatric intensive care unit after cardiac surgery, as a marker of disease severity in bronchiolitis, or as an indicator of lung involvement from SARS-CoV-2 infection are speculative and not yet supported by solid evidence. Lung ultrasound with the quantitative B-lines assessment is promising. The current evidence allows to use the quantification of B-lines in a limited number of neonatal and paediatric diseases.

Exogenous pulmonary surfactant in COVID-19 ARDS. The similarities to neonatal RDS suggest a new scenario for an ‘old’ strategy

Acute respiratory distress syndrome (ARDS) related to SARS-CoV-2 infection has some unusual characteristics that differentiate it from the pathophysiology described in the more ‘typical’ ARDS. Among multiple hypotheses, a close similarity has been suggested between COVID-19 ARDS and neonatal respiratory distress syndrome (RDS). With this opinion paper, we investigated the pathophysiological similarities between infant respiratory diseases (RDS and direct neonatal ARDS (NARDS)) and COVID-19 in adults. We also analysed, for the first time, similarities in the response to exogenous surfactant administration in terms of improved static compliance in RDS and direct NARDS, and adult COVID-19 ARDS. In conclusion, we believe that if the pathological processes are similar both from the pathophysiological point of view and from the response in respiratory mechanics to a recruitment treatment such as surfactant, perhaps the latter could be considered a plausible option and lead to recruitment in clinical trials currently ongoing on patients with COVID-19.

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, opening to innovative therapeutic avenues for the treatment of several respiratory diseases.

Pulmonary Hemorrhage in the Neonate

Pulmonary hemorrhage (PH) is a pathology associated with significant morbidity and mortality, particularly among preterm infants in the NICU. The diagnosis is made when hemorrhagic secretions are aspirated from the trachea concurrent with respiratory decompensation that necessitates intubation or escalated support. The implementation of mechanical ventilation and widespread exogenous surfactant administration have significantly reduced respiratory morbidities. However, when PH develops, death remains the most common outcome. Treatment for PH remains primarily supportive; thus, a thorough understanding of underlying disease processes, manifestations, diagnostic testing, and current evidence is vital to enable early identification and proactive management to reduce morbidity and mortality.

The Role of Alveolar Edema in COVID-19

The coronavirus disease 2019 (COVID-19) has spread over the world for more than one year. COVID-19 often develops life-threateninghypoxemia. Endothelial injury caused by the viral infection leads to intravascular coagulation and ventilation–perfusion mismatch. However, besides above pathogenic mechanisms, the role of alveolar edema in the disease progression has not been discussed comprehensively. Since the exudation of pulmonary edema fluid was extremely serious in COVID-19 patients, we bring out a hypothesis that severity of alveolar edema may determine the size of poorly-ventilated area and the blood oxygen content. Treatments to pulmonary edema (conservative fluid management, exogenous surfactant replacementsand ethanol–oxygen vapor therapyhypothetically) may be greatly helpful for reducingthe occurrences of severe cases. Given that late mechanical ventilation may causemucus (edema fluid) to be blown deep intothe small airways,oxygentherapy should be given at the early stages. Theoptimaltimeand blood oxygen saturation (SpO2) thresholdforoxygentherapy are also discussed.

Surfactant-Assisted Distal Pulmonary Distribution of Budesonide Revealed by Mass Spectrometry Imaging

Direct lung administration of budesonide in combination with surfactant reduces the incidence of bronchopulmonary dysplasia. Although the therapy is currently undergoing clinical development, the lung distribution of budesonide throughout the premature neonatal lung has not yet been investigated. Here, we applied mass spectrometry imaging (MSI) to investigate the surfactant-assisted distal lung distribution of budesonide. Unlabeled budesonide was either delivered using saline as a vehicle (n = 5) or in combination with a standard dose of the porcine surfactant Poractant alfa (n = 5). These lambs were ventilated for one minute, and then the lungs were extracted for MSI analysis. Another group of lambs (n = 5) received the combination of budesonide and Poractant alfa, followed by two hours of mechanical ventilation. MSI enabled the label-free detection and visualization of both budesonide and the essential constituent of Poractant alfa, the porcine surfactant protein C (SP-C). 2D ion intensity images revealed a non-uniform distribution of budesonide with saline, which appeared clustered in clumps. In contrast, the combination therapy showed a more homogeneous distribution of budesonide throughout the sample, with more budesonide distributed towards the lung periphery. We found similar distribution patterns for the SP-C and budesonide in consecutive lung tissue sections, indicating that budesonide was transported across the lungs associated with the exogenous surfactant. After two hours of mechanical ventilation, the budesonide intensity signal in the 2D ion intensity maps dropped dramatically, suggesting a rapid lung clearance and highlighting the relevance of achieving a uniform surfactant-assisted lung distribution of budesonide early after delivery to maximize the anti-inflammatory and maturational effects throughout the lung.

Exogenous surfactant in the late respiratory phase of COVID-19

The article presents data on the course of inhalations with a native surfactant administered in two patients (66 and 53 years old) at the late respiratory phase of the new coronavirus infection of COVID-19 (the 22nd and the 19th days from the disease onset) who received non-invasive artificial lung ventilation.Subjects and methods. For inhalations, an AeroNeb™ micropump nebulizer was used; for one inhalation, 75 mg of surfactant-BL was dissolved in 5 ml of isotonic sodium chloride solution. The treatment course included 5 days with 2 inhalations a day.Results. In both patients, upon the end of this therapy with the native surfactant, regression of respiratory failure was noted, the level of respiratory support was reduced to insufflation with humidified oxygen, and rehabilitation measures were started with subsequent discharge from the hospital.

Administration of exogenous surfactant and cytosolic phospholipase A2α inhibitors may help COVID-19 infected patients with chronic disease

Background : Cronavirus-19 (COVID-19) pandemic is a worldwide public health problem causing 347,070 deaths from December 25, 2019 until 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 suppressed viral attachment to the plasma membrane and subsequent replication in lung cells. Phosphatidylglycerol depletion caused by over expression of cytosolic phospholipase A2α induce lipid accumulation in lung alveoli and promote acute respiratory distress syndrome (ARDS). Exogenous-surfactant replacement has been successfully achieved in ARDS and improve oxygenation and lung mechanics. Inhibition of cytosolic phospholipase A2alpha impairs an early step of COVID-19 replication. Aim: The present study was carried out to explain the correlation between the administration of exogenous artificial surfactant as well as cytosolic phospholipase A2α inhibitors to improve oxygenation and lung mechanics and inhibit COVID-19 replication. Methods: Database research was carried out on Medline, Embase, Cochrane Library, country specific journals, and following-up WHO reports published between December 25, 2019 – May 25, 2020. Results: Till 25 May 2020, Coronavirus cases; 5,307,298, deaths; 347,070, recovered; 2,314,849. According to the WHO reports, most COVID-19 deaths seen are in people suffered from other chronic diseases characterized by phospholipidosis and phosphatidylglycerol deficiency, included hypertension, liver, heart, lung, and diabetes diseases. 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 A2α 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: The present study was showed that there is 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 cytosolic phospholipase A2α inhibitors and exogenous administration of a specific phospholipid surfactant.