Human Surfactant Proteins (SP-) A1 and SP-A2: to Include or Not in Surfactant Replacement Therapy, and If Yes, Both or Which One?

Abstract

Based on a large number of animal studies, surfactant protein A plays important roles in lung innate immunity under basal conditions and in response to various insults such as infection and oxidative stress. SP-A interacts with the Alveolar Macrophage (AM), the sentinel cell of innate immunity, and regulates many of its functions. These include the ability of the AM to produce cytokines and to carry out phagocytosis of various pathogens. Moreover, the AM proteomic expression profile has been shown to be significantly affected by SP-A. In a study where SP-A -/-mice were treated (or rescued) in vivo with a single dose of human SP-A, the treatment nearly restored the AM proteomic expression to that of the wild type [1], supporting a role of SP-A on AM protein expression. Among the protein groups affected were actin-related/cytoskeletal proteins, which was the major group, proteins regulating inflammatory processes, and proteins related to Nrf2-mediated oxidative stress. Of interest, earlier studies have also indicated a role for SP-A in actin filament dynamics via its ability to enhance cell migration and AM chemotaxis [2], phagocytosis [3], other actin-dependent processes [4][5][6] and F-actin assembly [7]. The actin cytoskeleton is highly regulated and dynamic, with globular (G) and filamentous (F) actin, under the influence of many actin binding proteins, constantly changing by polymerization, depolymerization, branching, and remodeling, modulating inflammatory response and oxidative stress ( Figure 1). Figure, signaling via NF-kB [8] and Nrf2 [9] can both depend on cytoskeletal changes, indicating that SP-A-mediated modulation of the actin cytoskeleton could have significant effects on AM responses. Moreover, the SP-A -/-rescue experiment [1] points to the possibility and feasibility of using SP-A as a therapeutic intervention in lung diseases influenced by innate immunity. Furthermore, based on animal studies [10] where small amounts of SP-A elicited significant differences in the AM proteome, it is possible that the SP-A amount needed may not be high, although, further experimentation will be needed to determine optimal amount and efficacy in the clinical setting. As shown inHowever, humans, (unlike rodents) have two genes, SFTPA1 (SP-A1) and SFTPA2 (SP-A2) with several genetic variants identified for each SP-A1 and SP-A2 gene. These variants have been associated with many lung diseases including neonatal diseases, such as Respiratory Distress Syndrome (RDS) and Bronchopulmonary Dysplasia (BPD) [11]. The SP-A1 and SP-A2 gene products have been shown to differ in several functions related to innate immunity [12] and in surfactantrelated functions [13,14]. These differences have been reviewed previously [12] and include differences in their oligomerization status [13,15,16], their ability to form phospholipid monolayers [17], their ability to bind sugars [18], and their ability to enhance the phagocytic activity and cytokine production by the alveolar macrophages and macrophage-like cell lines, respectively [3,...

Human Surfactant Protein SP-A1 and SP-A2 Variants Differentially Affect the Alveolar Microenvironment, Surfactant Structure, Regulation and Function of the Alveolar Macrophage, and Animal and Human Survival Under Various Conditions

“…On a final note, the use of SP-A in the clinic, and especially in the prematurely born infants who may develop respiratory distress syndrome or bronchopulmonary dysplasia has not been considered (165). These infants exhibit not only pulmonary surfactant deficiency (166), but also SP-A deficiency (67,167,168).…”

Surfactant Protein-A Function: Knowledge Gained From SP-A Knockout Mice

“…Moreover, current experience indicates that surfactant treatment of babies with "simple" RDS or with infection is less efficacious (93,94) or conclusions could not be reached for near-term or term infants with true or suspected bacterial infection (95). Thus, inclusion of SP-A in surfactant preparations (96) or usage by itself to treat not only premature infants, but individuals with a variety of conditions as suggested by the animal studies reviewed here warrants consideration. Moreover, the potential use of SP-A or functional fragments of SP-A for therapy (46,72,97) as it may relate to the current Covid-19 pandemic may be a plausible consideration.…”