Impact of Surfactant Protein-A Variants on Survival in Aged Mice in Response to Klebsiella pneumoniae Infection and Ozone: Serendipity in Action

Abstract

Innate immune molecules, SP-A1 (6A2, 6A4) and SP-A2 (1A0, 1A3), differentially affect young mouse survival after infection. Here, we investigated the impact of SP-A variants on the survival of aged mice. hTG mice carried a different SP-A1 or SP-A2 variant and SP-A-KO were either infected with Klebsiella pneumoniae or exposed to filtered air (FA) or ozone (O3) prior to infection, and their survival monitored over 14 days. In response to infection alone, no gene- or sex-specific (except for 6A2) differences were observed; variant-specific survival was observed (1A0 > 6A4). In response to O3, gene-, sex-, and variant-specific survival was observed with SP-A2 variants showing better survival in males than females, and 1A0 females > 1A3 females. A serendipitous, and perhaps clinically important observation was made; mice exposed to FA prior to infection exhibited significantly better survival than infected alone mice. 1A0 provided an overall better survival in males and/or females indicating a differential role for SP-A genetics. Improved ventilation, as provided by FA, resulted in a survival of significant magnitude in aged mice and perhaps to a lesser extent in young mice. This may have clinical application especially within the context of the current pandemic.

Can Prophylactic High Flow of Humidified and Warmed Filtered Air Improve Survival from Bacterial Pneumonia and SARS-CoV-2 in Elderly Individuals? The Role of Surfactant Protein A

“…Here, we discuss a serendipitous observation we made in a study investigating survival in aged mice after bacterial infection [ 1 ]. Specifically, we discuss the application of this finding to the human context and explore the potential for reducing disease severity and improving survival in individuals at risk for bacterial and viral pneumonias.…”

“…In humans (unlike in rodents), there are two SP-A genes, SFTPA1 and SFTPA2 , encoding SP-A1 and SP-A2, respectively; several genetic variants that may impact function have been identified for each [ 11 , 12 , 13 , 14 , 15 ]. Human surfactant proteins (SP)-A1 and SP-A2 genetic variants differentially affect several processes of the alveolar macrophage at baseline or in response to various insults [ 1 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. They also differentially affect lung function and survival of the organism, as shown by various animal models of bacterial infection and oxidative stress [ 1 , 24 , 25 ].…”

“…Human surfactant proteins (SP)-A1 and SP-A2 genetic variants differentially affect several processes of the alveolar macrophage at baseline or in response to various insults [ 1 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. They also differentially affect lung function and survival of the organism, as shown by various animal models of bacterial infection and oxidative stress [ 1 , 24 , 25 ]. These SP-A variants have been associated with differences in the susceptibility or degree of severity of various pulmonary diseases [ 26 , 27 , 28 , 29 , 30 ].…”

“…In our recent study [ 1 ] evaluating the correlation of SP-A variants with survival in aged mice after bacterial infection, we encountered a serendipitous finding. In this experimental model of Klebsiella pneumoniae infection in aged mice, we observed that mice exposed to high flow of humidified and warmed filtered air (FA) prior to infection had a better survival rate than the mice in normal room air [ 1 ]. This was the case for all humanized transgenic mice expressing different human SP-A variants, as well as in mice that lacked SP-A.…”

SNP and Haplotype Interaction Models Reveal Association of Surfactant Protein Gene Polymorphisms With Hypersensitivity Pneumonitis of Mexican Population

“…More importantly, we have shown an association of SP gene polymorphisms with IPF (13), COPD (14), and tuberculosis (21) in the Mexican population. Furthermore, some of the common SP-A variants have been shown to differentially affect function (22,23) and regulation (24)(25)(26)(27) of alveolar macrophages in an animal model, as well as SP-A variants have been associated with differential lung function mechanics and survival of mice (28)(29)(30). For the current study, we selected from physiologically and biologically relevant genes, 17 well-characterized SP SNPs that have been shown to associate with various acute and chronic Abbreviations: HP, Hypersensitivity Pneumonitis; SFTPA1, gene encoding SP-A1; SFTPA2, gene encoding SP-A2; SFTPB, gene encoding SP-B; SFTPC, gene encoding SP-C; SFTPD, gene encoding SP-D; SNPs, Single nucleotide polymorphisms; IPF, Interstitial pulmonary fibrosis; COPD, Chronic obstructive pulmonary disease; RDS, Respiratory distress syndrome; OR, Odds ratio.…”