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The role of lipocalin-2 in pneumonia associated acute respiratory distress syndrome

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Abstract
Introduction: Lipocalin-2 (LCN2) is a protein exressed in varius tissues and has a role in iron homeostasis, control of infection, and modulation of inflammation. The role of LCN2 in experimental acute lung injury model and its clinical significance in patients with pneumonia/acute respiratory distress syndrome (ARDS) has not been fully elucidated. The aim of study was to investigate the role of LCN2 using the experimental acute lung injury model and evaluate clinical significance of serum level of LCN2 in patients with pneumonia/ARDS.
Materials and Methods: Twenty-week-old male LCN2 knockout (KO) and wild type (WT) littermates, both in a C57BL/6 background, were used for the experiments. 1 mg/kg lipopolysaccharide (LPS) as experimental group and saline as control were injected through intratracheal method. In 24 hours later, mice were sacrificed and samples including serum, bronchoalveolar lavage fluid (BALF) and lung tissue were obtained. Mortality between LCN2KO and WT was observed along findings of BALF and lung tissue 8 days after intratracheal LPS (5mg/kg) treatment. Patients with pneumonia/ARDS who admitted to medical intensive care unit (MICU) and received invasive mechanical ventilation were included prospectively. Their serum LCN2 level s collected within 24 hours of MICU admission were measured using enzyme-linked immunosorbent assay.
Results: In LPS injected experiment, serum IL-1β and IL-6 levels were lower in LPS treated-LCN2KO mice than in WT. The recruitment of neutrophil and macrophage into alveoli was significantly lower in LPS treated-LCN2 KO mice than WT. In western blotting of lung tissue, the expressions of IL-6, phosphylated STAT3 and NF-κB were lower in LPS-treated LCN2KO mice compared to LPS-treated WT. Iron uptake of macrophages in BALF and lung tissues were lower in LPS-treated LCN2KO mice compared to LPS-treated WT. 22.2%(2/9) LPS(5mg/kg)-treated LCN2KO mice died during 8-days while all 14 WT survived. Macrophages and neutrophils in BALF and lung were more recruited in LPS-treated LCN2KO mice while activation of NF-κB did not differ.
In 27 patients with pneumonia/ARDS, Median serum LCN2 level was 177.2 ng/ml [Interquartile range (IQR), 108.5-306.9 ng/ml], which was significantly higher than 23 normal controls [44.8 ng/ml (IQR, 30.2-64.1 ng/ml), P <0.001]. Median serum LCN2 level was significantly lower in patients with pneumonia/ARDS than that of non-pneumonia/ARDS [263.5 ng/ml (233.5-469.6 ng/ml), P=0.044]. In 27 patients with pneumonia/ARDS, serum levels of LCN2 in 14 patients with acute kidney injury (AKI) was significantly higher than 13 those without AKI [284.7 ng/ml (IQR, 171.2-427.1ng/ml) vs 122.8 ng/ml (IQR, 72.6-176.2 ng/ml), P=0.003]. There was significantly higher LCN2 levels in 16 patients with shock than those without. [284.7 ng/ml (IQR, 124.7-413.2 ng/ml) vs 153.5 ng/ml (IQR, 69.6-177.2ng/ml) , P=0.009]. Serum LCN2 level was positively correlated to SOFA score (r=0.467,P<0.014) and procalcitonin (r=0.523, P=0.007). There was no significant difference between non-survivors and survivors at 30-day mortality [255.8 ng/ml (IQR, 135.4-404.8 ng/ml) in 10 non-survivors vs 168.7 ng/ml (IQR, 108.1-282.2 ng/ml) in 17 survivors, P=0.282]. Area under the receiver operating characterstics for LCN2 to predict 30-day mortality was 0.629 [95% confidence interval (CI), 0.423-0.806, P=0.279].
Conclusions: LCN2 deficiency induce less inflammatory reponse at 24 hours time point after intratracheal LPS treatment. At 8 days time point, its deficiency recruit more macrophages and neutrophils and induce more inflammation response in lung and contributes to substantial mortality without NF-κB activation. Serum LCN2 is associated with organ dysfunction in patients with pneumonia/ARDS but does not predict 30-day mortality.
Author(s)
유정완
Issued Date
2020
Awarded Date
2020-08
Type
Dissertation
URI
https://oak.ulsan.ac.kr/handle/2021.oak/6354
http://ulsan.dcollection.net/common/orgView/200000333567
Alternative Author(s)
Jung-Wan Yoo
Affiliation
울산대학교
Department
일반대학원 의학과
Advisor
홍상범
Degree
Doctor
Publisher
울산대학교 일반대학원 의학과
Language
eng
Rights
울산대학교 논문은 저작권에 의해 보호받습니다.
Appears in Collections:
Medicine > 2. Theses (Ph.D)
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