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

Abstract

The human innate host defense molecules, SP-A1 and SP-A2 variants, differentially affect survival after infection in mice and in lung transplant patients. SP-A interacts with the sentinel innate immune cell in the alveolus, the alveolar macrophage (AM), and modulates its function and regulation. SP-A also plays a role in pulmonary surfactant-related aspects, including surfactant structure and reorganization. For most (if not all) pulmonary diseases there is a dysregulation of host defense and inflammatory processes and/or surfactant dysfunction or deficiency. Because SP-A plays a role in both of these general processes where one or both may become aberrant in pulmonary disease, SP-A stands to be an important molecule in health and disease. In humans (unlike in rodents) SP-A is encoded by two genes (SFTPA1 and SFTPA2) and each has been identified with extensive genetic and epigenetic complexity. In this review, we focus on functional, structural, and regulatory differences between the two SP-A gene-specific products, SP-A1 and SP-A2, and among their corresponding variants. We discuss the differential impact of these variants on the surfactant structure, the alveolar microenvironment, the regulation of epithelial type II miRNome, the regulation and function of the AM, the overall survival of the organism after infection, and others. Although there have been a number of reviews on SP-A, this is the first review that provides such a comprehensive account of the differences between human SP-A1 and SP-A2.

Single Nucleotide Polymorphisms Interactions of the Surfactant Protein Genes Associated With Respiratory Distress Syndrome Susceptibility in Preterm Infants

“…Despite the above limitations, this study indicates a greater role of SFTPA1 and SFTPA2 in RDS susceptibility as they had the most interactions with SNPs of other SFTPs in the two and three-SNP models. Furthermore, the concern for infection in the setting of prematurity and chorioamnionitis sets up the SFTPA1 and SFTPA2 gene products, SP-A1 and SP-A2, as very important molecules for the first line of defense and regulation of various processes of the alveolar macrophage ( 17 ). Our animal studies, among others, have shown that SP-A1 and SP-A2 regulate the miRNome of the alveolar macrophage ( 90 ) and the alveolar epithelial type II cells in response to ozone exposure ( 91 ).…”

“…Furthermore, it has been noted that infants dying with RDS have low levels of surfactant proteins (SP) ( 11 , 12 ). SP-A and SP-D are hydrophilic proteins and play an important role in innate immunity and the regulation of inflammatory processes and host defense ( 13 – 17 ). SP-B and SP-C are hydrophobic proteins that enhance the adsorption and spreading of surfactant phospholipid ( 18 ).…”

“…In addition to its host defense function, SP-A, along with SP-B, is important for the formation of tubular myelin (an extracellular surfactant structure) ( 22 – 24 ). Moreover, SP-A is involved in surfactant-related functions ( 17 , 25 ) and lung airway function ( 26 ).…”

“…Human SP-A, consisting of SP-A1 and SP-A2 proteins, is encoded by two functional genes SFTPA1 and SFTPA2 , respectively ( 41 ). The SFTPA1 and SFTPA2 genes share a high degree of sequence similarity but differ at various splice variants at the 5′ untranslated region (UTR) and exhibit sequence variability within coding and non-coding regions ( 17 ). Prior studies have also found intragenic and intergenic haplotypes between SFTPA1 and/or SFTPA2 ( 42 ) and SFTPB and/or SFTPD haplotypes associated with risk or protective effect in RDS ( 43 ).…”

Differential Regulation of Human Surfactant Protein A Genes, SFTPA1 and SFTPA2, and Their Corresponding Variants

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The human SFTPA1 and SFTPA2 genes encode the surfactant protein A1 (SP-A1) and SP-A2, respectively, and they have been identified with significant genetic and epigenetic variability including sequence, deletion/insertions, and splice variants. The surfactant proteins, SP-A1 and SP-A2, and their corresponding variants play important roles in several processes of innate immunity as well in surfactant-related functions as reviewed elsewhere [1]. The levels of SP-A have been shown to differ among individuals both under baseline conditions and in response to various agents or disease states.

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