Pneumonia and sepsis are major risk factors for acute kidney injury (AKI). Patients with pneumonia and AKI are at increased risk for morbidity and mortality. Surfactant protein D (SP-D) expressed in lung and kidney plays important roles in innate immunity. However, little is known about the role of organ-specific SP-D in the sepsis. The current study uses wild type (WT), SP-D knockout (KO), and humanized SP-D transgenic (hTG, lung-specific SP-D expression) mice to study organ-specific role of SP-D in pneumonia-induced sepsis. Analyses demonstrated differential lung and kidney injury among three-type mice infected with Pseudomonas aeruginosa. After infection, KO mice showed higher injurious scores in both lung and kidney, and decreased renal function than WT and hTG mice. hTG mice exhibited comparable lung injury but more severe kidney injury compared to WT mice. Increased renal tubular apoptosis, NF-κB activation and proinflammatory cytokines in the kidney of KO mice were found when compared with WT and hTG mice. Furthermore, in vitro primary proximal tubular epithelial cells from KO mice showed more apoptosis with higher level of activated caspase-3 than those from WT mice after LPS treatment. Collectively, SP-D attenuates AKI in the sepsis by modulating renal apoptosis, inflammation and NF-κB signaling.

Sepsis is a major cause of acute kidney injury (AKI) with high rates of morbidity and mortality. Surfactant proteins A and D (SP-A, SP-D) play a critical role in host defense and regulate inflammation during infection. Recent studies indicate SP-A and SP-D are expressed in the kidney. The current study examines the role of SP-A and SP-D in the pathogenesis of sepsis-induced AKI. Wild-type (WT) and SP-A/SP-D double knockout (KO) C57BL/6 mice were treated by cecal ligation and puncture (CLP) or sham surgery. Histological, cellular and molecular indices of kidney injury were investigated in septic mice 6 and 24 h after CLP. 24 h post-CLP, kidney injury was more severe, renal function was decreased, blood creatinine and BUN were higher in septic SP-A/SP-D KO mice (p<0.05, vs septic WT mice). Kidney edema and vascular permeability were increased in septic SP-A/SP-D KO mice (p<0.01, vs septic WT mice). Apoptotic cells increased significantly (p<0.01) in the kidney of septic SP-A/SP-D KO mice compared to septic WT mice. Molecular analysis revealed levels of Bcl-2 (an inhibitor of apoptosis) were lower and levels of caspase-3 (a biomarker of apoptosis) were higher in the kidney of septic SP-A/SP-D KO mice (p<0.01, vs septic WT mice). Furthermore, levels of NF-κB and phosphorylated IκB-α increased significantly in the kidney of septic SP-A/SP-D KO mice than septic WT mice, suggesting SP-A/SP-D KO mice have a more pronounced inflammatory response to sepsis. We conclude SP-A and SP-D attenuate kidney injury by modulating inflammation and apoptosis in sepsis-induced AKI.

To investigate the effects of surfactant proteins A and D (SP-A, SP-D) in urinary tract infection (UTI), SP-A and SP-D double knockout (SP-A/D KO) and wild type (WT) C57BL/6 female mice were infected with uropathogenic Escherichia coli by intravesical inoculation. Compared with WT mice SP-A/D KO mice showed increased susceptibility to UTI as evidenced by higher bacterial CFU, more infiltrating neutrophils and severe pathological changes. Keratinocyte-derived chemokine increased in the kidney of WT mice but not in SP-A/D KO mice 24 h post-infection. Compared to control, level of IL-17 was elevated in the kidney of infected WT and SP-A/D KO mice and the level of IL-17 was higher in the infected SP-A/D KO mice than infected WT mice 24 and 48 h post-infection. Basal level of p38 MAPK phosphorylation in SP-A/D KO mice was higher compared to WT mice. Phosphorylated-p38 level was elevated in the kidney of WT mice post-infection but not in SP-A/D KO mice. Furthermore, in vitro growth of uropathogenic E. coli was inhibited by SP-A and SP-D. We conclude that SP-A and SP-D function as mediators of innate immunity by inhibiting bacterial growth and modulating renal inflammation in part by regulating p38 MAPK-related pathway in murine UTI.

No abstract