Exogenous pulmonary surfactant: A review focused on adjunctive therapy for severe acute respiratory syndrome coronavirus 2 including SP-A and SP-D as added clinical marker

Abstract

Type I and type II pneumocytes are two forms of epithelial cells found lining the alveoli in the lungs. Type II pneumocytes exclusively secrete 'pulmonary surfactants,' a lipoprotein complex made up of 90% lipids (mainly phospholipids) and 10% surfactant proteins (SP-A, SP-B, SP-C, and SP-D). Respiratory diseases such as influenza, severe acute respiratory syndrome coronavirus infection, and severe acute respiratory syndrome coronavirus 2 infection are reported to preferentially attack type II pneumocytes of the lungs. After viral invasion, consequent viral propagation and destruction of type II pneumocytes causes altered surfactant production, resulting in dyspnea and acute respiratory distress syndrome in patients with coronavirus disease 2019. Exogenous animal-derived or synthetic pulmonary surfactant therapy has already shown immense success in the treatment of neonatal respiratory distress syndrome and has the potential to contribute efficiently toward repair of damaged alveoli and preventing severe acute respiratory syndrome coronavirus 2-associated respiratory failure. Furthermore, early detection of surfactant collectins (SP-A and SP-D) in the circulatory system can be a significant clinical marker for disease prognosis in the near future.

Keywords: ARDS; COVID-19; Collectin; Pulmonary surfactant; SARS-CoV-2; Toll-like receptor, TLR; acute respiratory distress syndrome, ARDS; angiotensin-converting enzyme 2, ACE2; coronavirus disease 2019, COVID-19; dipalmitoylphosphatidylcholine, DPPC; human immunodeficiency virus, HIV; interleukin, IL; palmitoyl-oleoyl-phosphatidylglycerol, POPG; phosphatidylinositol, PI; respiratory distress syndrome, RDS; severe acute respiratory syndrome coronavirus 2, SARS-CoV-2; surfactant proteins, SP; tumor necrosis factor, TNF.

Figure 1

Scheme of alveolar collapse due to COVID-19–mediated surfactant impairment and the role of exogenous pulmonary surfactant therapy. (a) Normal alveolus. (b) Pathophysiology of SARS-CoV-2 infection. After entry of SARS-CoV-2 in type II alveolar cells (1), the infected cell becomes defective for surfactant production and releases cytokines (2), which in turn activates alveolar macrophages (3) to release IL-1, IL-6, and TNF-α, and the level of these proinflammatory molecules rises; these molecules induce differentiation of natural killer (NK) cells and dendritic (D) cells, causing release of more proinflammatory response; cumulative effect leads to prolonged inflammatory response, and increased vasodilation causes influx of neutrophils and activated T cells in the alveolus from the capillary tube. The neutrophil produces ROS and proteinases (4), leading to further destruction of healthy type II cells (5); as a result, surfactant production decreases markedly, which in turn causes fluid accumulation in the alveolus leading to alveolar collapse and ARDS further; destruction of type II cells leads to leakage of SP-A and SP-D in the capillary, and their concentration becomes elevated in blood (6). (c) Alveolar collapse leading to the development of ARDS and MAS. (d) The probable mechanism of exogenous pulmonary surfactant therapy for pulmonary protection. ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; IL, interleukin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF-α, tumor necrosis factor alpha; ROS, reactive oxygen species; MAS, macrophage activation syndrome.