Investigating the Role of Surfactant Protein a in Acute and Chronic Neuroinflammation Using a Mouse Model

Background: The role of surfactant protein A (SP-A) in pulmonary immunity and attenuation of inflammation is well-established. SP-A has also been shown to modulate inflammation at extrapulmonary sites using various models of inflammatory disease. Expression of SP-A has previously been reported in rat and human brain. We hypothesized that SP-A may act as an immunomodulatory protein to attenuate both acute and chronic inflammation in the neonatal mouse brain.

Methods: mRNA isolated from wildtype (WT) and SP-A knockout (SP-A-/-) mice was subjected to RT-PCR analysis to detect SP-A expression in both brain and lung tissue. Two models of neonatal brain inflammation were used in WT and SP-A-/- neonatal mice at DOL 7: acute (sepsis) and chronic (hypoxic-ischemic encephalopathy, or HIE). For the sepsis model, lipopolysaccharide (LPS) or saline (as control) was intraperitoneally injected. Pups were euthanized 4 hours or 24 hours following injection, and mRNA was isolated from brain tissue. For the HIE model, pups underwent unilateral common carotid artery ligation or sham surgery followed by exposure to systemic hypoxia. Pups were euthanized 7 days following surgery, and mRNA was isolated from brain tissue. Cytokine expression (IL-1β, IL-6, CXCL1, IL-10 and TNF-) was then determined by real-time quantitative RT-PCR analysis.

Results: While SP-A mRNA was detected in lung tissue of WT mice, it was not detected in the brains of either WT or SP-A-/- mice. At 4 and 24 hours post-LPS injection, expression of all pro-inflammatory cytokine mRNAs were significantly increased in the brain compared to saline injection in both WT and SP-A-/- mice. Expression of cytokine mRNAs was increased in the brains of SP-A-/- mice compared with WT mice at both 4 hours and 24 hours following LPS injection. At 7 days post-HIE surgery, expression of CXCL1 and TNF-α were also significantly increased in the brains of SP-A-/- mice compared with WT mice. However, expression of IL-6 and IL-10 were significantly decreased in the brains of SP-A-/- mice compared with WT mice.

Conclusion: While we could not detect SP-A expression in murine brain tissue, neonatal mice deficient in SP-A had a significantly greater cytokine expression in the brain compared to neonatal WT mice following exposure to LPS, suggesting acute attenuation of inflammation by SP-A. However, in a model of chronic inflammation (i.e., HIE), only CXCL1 and TNF-α were increased in SP-A deficient mice compared to WT mice, suggesting that attenuation of chronic inflammation by SP-A may be limited to certain inflammatory pathways.