Relevance And Function Of Insulin Like Growth Factor Binding Protein-6 In Sepsis Of Pneumonia

Background:Sepsis is up to date defined as organ dysfunction resulting from a dysregulated host response to infection,with a high number of morbid deaths and mortality.Early diagnosis and treatment of sepsis remains a major challenge.The mechanisms by which sepsis leads to dysfunction of various organs were not explored,and there is no effective treatment.In order to solve the problem of sepsis,it is particularly important to explore the research of sepsis pathogenesis.Insulin like growth factor binding protein 6(IGFBP-6)is widely expressed in multiple tissues and is involved in the inhibition of proliferation,inhibition of angiogenesis,and increased oxidative burst and degranulation of neutrophils.Currently,the focus of research on IGFBP-6 is on malignancy related diseases,such as rhabdomyosarcoma,lung,breast,prostate and colon cancer.Furthermore,although the role of IGFBP-6 in inflammation is beginning to be noted,the relationship of IGFBP-6 to the pathological course of infectious diseases,especially sepsis,has not been explored.In our previous study,agonal plasma IGFBP-6 levels were found to be significantly higher in plasma samples collected within 24 hours before death from sepsis during the remission phase by protein quantitative mass spectrometry.This suggests that IGFBP-6 may play a key role in the disease course and prognosis of sepsis.To define the role and impact of plasma IGFBP-6 levels in sepsis,we collected plasma samples from healthy subjects(healthy),community-acquired pneumonia(CAP),pneumonia induced sepsis(PIS),digestive related infection induced sepsis(DIS),infection of digestive system without sepsis(DI).We further explored the role of IGFBP-6 in the disease course of sepsis by exploring the relationship between IGFBP-6 and dysfunction in various organs of sepsis and by follow-up animal models and in vitro cell experiments.Methods:This study selected patients with a definite diagnosis of sepsis due to pneumonia,patients with sepsis due to digestive system infection who were admitted to the respiratory and critical care unit of Huai He hospital,Henan University,from June 2016 to June 2019,and patients with community-acquired pneumonia who were admitted during the same period,as well as healthy individuals,and collected patients with sepsis due to digestive system infection from June 2020 to September 2020 from the Department of Gastroenterology,Huai He hospital,Henan University,from June 2020 to September 2020 And patients with digestive system infection without sepsis were included in the study.Enzyme linked immunosorbent assay(ELISA)was used to measure the IGFBP-6 levels in plasma samples from different groups,which were grouped for comparison.At the same time,the clinical data corresponding to different groups of samples,such as age,gender,duration of hospitalization,prognosis,and comorbidities,were collected,and the results of each clinical test were analyzed.In addition,we observed the mortality of LPS-versus KPS mice after intravenous administration of murine IGFBP-6 by constructing a mouse model of toxemia(LPS),as well as a Klebsiella pneumoniae sepsis(KPS)model,and collected blood,organs for in vitro analysis,combined with in vitro cell experiments to explore the mechanism of IGFBP-6 in the disease course of sepsis.Results:1.There were no significant differences in plasma IGFBP-6 levels between Healthy,CAP,DIS and DI patients;Plasma IGFBP-6 levels were significantly higher in PIS patients compared to healthy,CAP patients;2.Among patients with PIS,those with combined moderate severe renal impairment had much higher plasma IGFBP-6 levels than did those with other conditions,and those with combined congestive heart failure had higher plasma IGFBP-6 levels than did those with hemiplegia.3.The plasma IGFBP-6 level showed an increasing trend as the total SOFA score increased;4.Among patients with PIS,those who developed septic shock had significantly higher plasma IGFBP-6 levels than did nonshockable patients;Patients who died within 30 days had significantly higher plasma IGFBP-6 levels than those who survived,and this phenomenon was evident only in males;5.Among patients with PIS,the AUC values were 0.615 for IGFBP-6 to predict mortality and 0.646 for predicting the development of septic shock;The AUC value for predicting renal impairment was 0.885;6.In patients with PIS,higher plasma IGFBP-6 levels predicted a greater risk of mortality,and this phenomenon was evident only in men;7.IGFBP-6 was more frequently associated with renal impairment in sepsis,and it was significantly higher as renal impairment worsened in patients with sepsis,and negatively correlated with the number of red blood cells,hemoglobin content,and hematocrit;8.Intravenous administration of murine IGFBP-6 significantly improved survival and significantly reduced the area of lung consolidation in KPS mice;9.Intravenous administration of murine IGFBP-6 significantly reduced the survival of LPS treated mice;10.IGFBP-6 attenuates nitric oxide release and cell death of macrophages upon lipopolysaccharide stimulation;11.It is possible that IGFBP-6 may regulate the phagocytic ability of macrophages to control K.pneumoniae phagocytosis.Conclusion:(1)The level of plasma IGFBP-6 has potential value for the diagnosis of sepsis due to pneumonia;(2)Plasma IGFBP-6 is a potential male sepsis prognostic marker;(3)The concentration of plasma IGFBP-6 is helpful in predicting renal function injury in sepsis;(4)Increased levels of plasma IGFBP-6 contribute to the improvement of patients with sepsis due to pneumonia,and this effect has the potential to be achieved by regulating the function of innate immune cells.