Impact of Ozone, Sex, and Gonadal Hormones on Bronchoalveolar Lavage Characteristics and Survival in SP-A KO Mice Infected with Klebsiella pneumoniae.

Chintan K Gandhi,Guirong Wang,David S Phelps,Joanna Floros,Todd M Umstead,Faryal Durrani,Anatoly N Mikerov,Sanmei Hu

doi:10.3390/microorganisms8091354

Abstract

Surfactant protein A (SP-A) plays an important role in innate immunity. The sex-dependent survival of infected SP-A knockout (KO) mice has been observed. Our goal was to study the impact of ozone (O3) and sex, as well as gonadal hormones, on the bronchoalveolar lavage (BAL) readouts and survival, respectively, of Klebsiella pneumoniae-infected SP-A KO mice. Male and female SP-A KO mice were exposed to O3 or filtered air and infected with K. pneumoniae. We studied markers of inflammation and tissue damage at 4, 24, and 48 h, as well as the survival over 14 days, of gonadectomized (Gx) mice implanted with control pellets (CoP) or hormone (5α-dihydrotestosterone (DHT) in female gonadectomized mice (GxF) or 17β-estradiol (E2) in male gonadectomized mice (GxM)). We observed: (1) an increase in neutrophil and macrophage inflammatory protein-2 levels as time progressed post-infection, and O3 exposure appeared to increase this response; (2) an increase in lactate dehydrogenase, total protein, oxidized protein, and phospholipids in response to O3 with no consistent sex differences in studied parameters; and (3) a reduction in survival of the GxM and CoP mice, the GxM and E2 mice, and the GxF and DHT mice but not for the GxF and CoP mice after O3. Without SP-A, (a) sex was found to have a minimal impact on BAL cellular composition and tissue damage markers, and (b) the impact of gonadal hormones on survival was found to involve different mechanisms than in the presence of SP-A.

Highlights

Pneumonia is the most common infectious cause of childhood mortality globally [1] and a leading cause of death worldwide [2]
We performed two major groups of experiments: (1) we measured a number of parameters to study sequential changes in the bronchoalveolar lavage (BAL) of surfactant protein A (SP-A) KO male and female mice at 4, 24, and 48 h after exposure to either O3 or filtered air (FA) and K. pneumoniae infection, and (2) we measured the effect of gonadal hormones on the survival of K. pneumoniae-infected SP-A KO mice after exposure to O3 or FA
There was a progressive increase in %PMNs as the time lapsed after infection in both FA- and O3-exposed mice (Figure 1A) in both sexes

Summary

Introduction

Pneumonia is the most common infectious cause of childhood mortality globally [1] and a leading cause of death worldwide [2]. Among various immune-related functions, SP-A has been shown to enhance the clearance of pathogens by acting as an opsonin [11,13], participating in the development of dendritic cells [14], regulating the production of cell surface antigens [15], and controlling reactive oxygen species (ROS) [16,17,18] Deficits in these functions in SP-A knockout (KO) mice makes them more susceptible to pneumonia resulting from various infectious agents such as Pseudomonas aeruginosa [19], group B Streptococcus [20], Haemophilus influenzae [20], and K. pneumoniae [4] than wild type mice. The underlying mechanism(s) by which SP-A, gonadal hormones, and sex exert these effects are not well-understood

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Conclusion