Acute respiratory distress syndrome: focusing on secondary injury / 中华医学杂志(英文版)

Acute respiratory distress syndrome (ARDS) is one of the most common severe diseases seen in the clinical setting. With the continuous exploration of ARDS in recent decades, the understanding of ARDS has improved. ARDS is not a simple lung disease but a clinical syndrome with various etiologies and pathophysiological changes. However, in the intensive care unit, ARDS often occurs a few days after primary lung injury or after a few days of treatment for other severe extrapulmonary diseases. Under such conditions, ARDS often progresses rapidly to severe ARDS and is difficult to treat. The occurrence and development of ARDS in these circumstances are thus not related to primary lung injury; the real cause of ARDS may be the "second hit" caused by inappropriate treatment. In view of the limited effective treatments for ARDS, the strategic focus has shifted to identifying potential or high-risk ARDS patients during the early stages of the disease and implementing treatment strategies aimed at reducing ARDS and related organ failure. Future research should focus on the prevention of ARDS.

Induction and deduction in sepsis-induced cardiomyopathy: five typical categories / 中华医学杂志(英文版)

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The heart is one of the most important oxygen delivery organs, and dysfunction significantly increases the mortality of the body. Hence, the heart has been studied in sepsis for over half a century. However, the definition of sepsis-induced cardiomyopathy is not unified yet, and the conventional conception seems outdated: left ventricular systolic dysfunction (LVSD) along with enlargement of the left ventricle, recovering in 7 to 10 days. With the application of echocardiography in intensive care units, not only LVSD but also left ventricular diastolic dysfunction, right ventricular dysfunction, and even diffuse ventricular dysfunction have been seen. The recognition of sepsis-induced cardiomyopathy is gradually becoming complete, although our understanding of it is not deep, which has made the diagnosis and treatment stagnate. In this review, we summarize the research on sepsis-induced cardiomyopathy. Women and young people with septic cardiomyopathy are more likely to have LVSD, which may have the same mechanism as stress cardiomyopathy. Elderly people with ischemic cardiomyopathy and hypertension tend to have left ventricular diastolic dysfunction. Patients with mechanical ventilation, acute respiratory distress syndrome or other complications of increased right ventricular afterload mostly have right ventricular dysfunction. Diffuse cardiac dysfunction has also been shown in some studies; patients with mixed or co-existing cardiac dysfunction are more common, theoretically. Thus, understanding the pathophysiology of sepsis-induced cardiomyopathy from the perspective of critical care echocardiography is essential.

Vimentin modulates apoptosis and inflammatory cytokine release by a human monocytic cell line (THP-1) in response to lipopolysaccharides in vitro / 中华医学杂志(英文版)

Background@#It has recently been recognized that serum vimentin is elevated in infectious diseases, and that vimentin plays a role in regulating neutrophils and macrophages associated inflammation. However, the mechanisms are unclear. This study was designed to explore the role of vimentin in regulating monocyte survival or apoptosis as well as inflammatory cytokine secretion in response to lipopolysaccharides (LPSs).@*Methods@#A human monocytic leukemia cell line (THP-1) was transfected with vimentin-specific small interfering RNA (siRNA) or vimentin over-expressing plasmid. Apoptosis was assessed by TdT-mediated dUTP Nick-End Labeling (TUNEL) and DNA content assay. Immunoblotting was performed to detect apoptosis-associated proteins. Cytokines (interleukin [IL]-6, IL-10, and tumor necrosis factor α [TNF-α]) were measured by enzyme-linked immuno sorbent assay. Two-way analysis of variance followed by Student’s t test was used to compare means between different groups.@*Results@#Suppression of vimentin in THP-1 cells resulted in increased apoptotic response in the presence of LPS, while overexpression of vimentin could prevent the cells from apoptosis in response to LPS. LPS alone or suppression of vimentin resulted in significant up-regulation of caspase-3 (1.42 ± 0.20 of LPS alone and 1.68 ± 0.10 of vimentin suppression vs. control, t = 5.21 and 10.28, respectively, P < 0.05). In addition, pro-inflammatory cytokines (IL-6 and TNF-α) was significantly increased (IL-6: 577.90 ± 159.90 pg/day/105 cells vs. 283.80 ± 124.60 pg/day/105 cells of control, t = 14.76, P < 0.05; TNF-α: 54.10 ± 5.80 vs. 17.10 ± 0.10 pg/day/105 cells of control, t = 6.71, P < 0.05), while anti-inflammatory cytokine (IL-10) was significantly up-regulated in the THP-1 cells that over-expressed vimentin (140.9 ± 17.2 pg/day/105 cells vs. undetectable in control cells).@*Conclusions@#In summary, the vimentin may regulate innate immunity through modulating monocytes viability as well as inflammatory response in sepsis through shifting the balance of pro-inflammatory and anti-inflammatory cytokines.

Early initiation renal replacement therapy for fluid management to reduce central venous pressure is more conducive to renal function recovery in patients with acute kidney injury / 中华医学杂志(英文版)

Background@#Acute kidney injury (AKI) is a serious complication in critically ill patients with septic shock treated in the intensive care unit. Renal replacement therapy (RRT) is a treatment for severe AKI; however, the time of initiation of RRT and factors that affect the recovery of kidney function remains unclear. This study was to explore whether early initiation of RRT treatment for fluid management to reduce central venous pressure (CVP) can help to improve patients’ kidney function recovery.@*Methods@#A retrospective analysis of septic patients who had received RRT treatment was conducted. Patients received RRT either within 12 h after they met the diagnostic criteria of renal failure (early initiation) or after a delay of 48 h if renal recovery had not occurred (delayed initiation). Parameters such as patients’ renal function recovery at discharge, fluid balance, and levels of CVP were assessed.@*Results@#A total of 141 patients were eligible for enrolment: 40.4% of the patients were in the early initiation group (57 of 141 patients), and 59.6% were in the delayed initiation group (84 of 141 patients). There were no significant differences in the characteristics at baseline between the two groups, and there were no differences in 28-day mortality between the two groups (χ2 = 2.142, P = 0.143); however, there was a significant difference in the recovery rate of renal function between the two groups at discharge (χ2 = 4.730, P < 0.001). More importantly, early initiation of RRT treatment and dehydration to reduce CVP are more conducive to the recovery of renal function in patients with AKI.@*Conclusion@#Compared with those who received delayed initiation RRT, patients who received early-initiation RRT for dehydration to reduce CVP have enhanced kidney function recovery.

Critical hemodynamic therapy oriented resuscitation helping reduce lung water production and improve survival / 中华医学杂志(英文版)

Background:@#Increased extravascular lung water (EVLW) in shock is common in the critically ill patients. This study aimed to explore the effect of cardiac output (CO) on EVLW and its relevant influence on prognosis.@*Methods:@#The hemodynamic data of 428 patients with pulse-indicated continuous CO catheterization from Department of Critical Care Medicine, Peking Union Medical College Hospital were retrospectively collected and analyzed. The patients were assigned to acute respiratory distress syndrome group, cardiogenic shock group, septic shock group, and combined shock (cardiogenic and septic) group according to their symptoms. Information on 28-day mortality and renal function was also collected.@*Results:@#The CO and EVLW index (EVLWI) in the cardiogenic and combined shock groups were lower than those in the other groups (acute respiratory distress syndrome group vs. cardiogenic shock group vs. septic shock group vs. combined shock group: CO, 5.1 [4.0, 6.2] vs. 4.7 [4.0, 5.7] vs. 5.5 [4.3, 6.7] vs. 4.6 [3.5, 5.7] at 0 to 24 h, P=0.009; 4.6 [3.8, 5.6] vs. 4.8 [4.1, 5.7] vs. 5.3 [4.4, 6.5] vs. 4.5 [3.8, 5.3] at 24 to 48 h, P=0.048; 4.5 [4.1, 5.4] vs. 4.8 [3.8, 5.5] vs. 5.3 [4.0, 6.4] vs. 4.0 [3.2, 5.4] at 48 to 72 h, P=0.006; EVLWI, 11.4 [8.7, 19.1] vs. 7.9 [6.6, 10.0] vs. 8.8 [7.4, 11.0] vs. 8.2 [6.7, 11.3] at 0 to 24 h, P < 0.001; 11.8 [7.7, 17.2] vs. 7.8 [6.3, 10.2] vs. 8.7 [6.6, 12.2] vs. 8.0 [6.6, 11.1] at 24 to 48 h, P < 0.001; and 11.3 [7.7, 18.7] vs. 7.5 [6.3, 10.0] vs. 8.8 [6.3, 12.2] vs. 8.4 [6.4, 11.2] at 48 to 72 h, P < 0.001. The trend of the EVLWI in the septic shock group was higher than that in the cardiogenic shock group (P < 0.05). Moreover, there existed some difference in the pulmonary vascular permeability index among the cardiogenic shock group, the septic shock group, and the combined shock group, without statistical significance (P > 0.05). In addition, there was no significant difference in tissue perfusion or renal function among the four groups during the observation period (P > 0.05). However, the cardiogenic shock group had a higher 28-day survival rate than the other three groups [log rank (Mantel-Cox) = 31.169, P < 0.001].@*Conclusion:@#Tissue-aimed lower CO could reduce the EVLWI and achieve a better prognosis.

Early initiation renal replacement therapy for fluid management to reduce central venous pressure is more conducive to renal function recovery in patients with acute kidney injury / 中华医学杂志(英文版)

BACKGROUND@#Acute kidney injury (AKI) is a serious complication in critically ill patients with septic shock treated in the intensive care unit. Renal replacement therapy (RRT) is a treatment for severe AKI; however, the time of initiation of RRT and factors that affect the recovery of kidney function remains unclear. This study was to explore whether early initiation of RRT treatment for fluid management to reduce central venous pressure (CVP) can help to improve patients' kidney function recovery.@*METHODS@#A retrospective analysis of septic patients who had received RRT treatment was conducted. Patients received RRT either within 12 h after they met the diagnostic criteria of renal failure (early initiation) or after a delay of 48 h if renal recovery had not occurred (delayed initiation). Parameters such as patients' renal function recovery at discharge, fluid balance, and levels of CVP were assessed.@*RESULTS@#A total of 141 patients were eligible for enrolment: 40.4% of the patients were in the early initiation group (57 of 141 patients), and 59.6% were in the delayed initiation group (84 of 141 patients). There were no significant differences in the characteristics at baseline between the two groups, and there were no differences in 28-day mortality between the two groups (χ = 2.142, P = 0.143); however, there was a significant difference in the recovery rate of renal function between the two groups at discharge (χ = 4.730, P < 0.001). More importantly, early initiation of RRT treatment and dehydration to reduce CVP are more conducive to the recovery of renal function in patients with AKI.@*CONCLUSION@#Compared with those who received delayed initiation RRT, patients who received early-initiation RRT for dehydration to reduce CVP have enhanced kidney function recovery.

A cross-sectional study of acute cor pulmonale in acute respiratory distress syndrome patients in China / 中华医学杂志(英文版)

BACKGROUND@#Increased right ventricle afterload during acute respiratory distress syndrome (ARDS) may induce acute cor pulmonale (ACP), which is associated with a poor clinical outcome. Echocardiography is now considered as a rapid and non-invasive tool for diagnosis of ACP. The aims of this study were to investigate the morbidity and mortality rates of ACP in ARDS patients in intensive care units (ICUs) across the mainland of China and to determine the severity and prognosis of ACP in ARDS patients through an ultrasound protocol (TRIP). And the association between ACP related factors and the ICU mortality will be revealed.@*METHODS@#This study is a multicenter and cross-sectional study in China which will include ICU participants when diagnosed as ARDS. The ultrasound protocol, known as the TRIP, is proposed as severity assessment for ACP, which includes tricuspid regurgitation velocity (T), right ventricular size (R), inferior vena cava diameter fluctuation (I), and pulmonary regurgitation velocity (P). The 28-day mortality, ICU/hospital mortality, the length of stay in ICU, mechanical ventilation days, hemodynamic parameters and lab parameters of liver function and kidney function are all recorded.@*DISCUSSION@#This large-scale study would give a sufficient epidemic investigation of ACP in ARDS patients in China. In addition, with the TRIP protocol, we expect that we could stratify ACP with more echocardiography parameters.@*TRIAL REGISTRATION@#NCT03827863, https://clinicaltrials.gov/ct2/show/NCT03827863.

Rules of anti-infection therapy for sepsis and septic shock / 中华医学杂志(英文版)

OBJECTIVE@#Sepsis is a deadly infection that causes injury to tissues and organs. Infection and anti-infective treatment are the eternal themes of sepsis. The successful control of infection is a key factor of resuscitation for sepsis and septic shock. This review examines evidence for the treatment of sepsis. This evidence is combined with clinical experiments to reveal the rules and a standard flowchart of anti-infection therapy for sepsis.@*DATA SOURCES@#We retrieved information from the PubMed database up to October 2018 using various search terms and their combinations, including sepsis, septic shock, infection, antibiotics, and anti-infection.@*STUDY SELECTION@#We included data from peer-reviewed journals printed in English on the relationships between infections and antibiotics.@*RESULTS@#By combining the literature review and clinical experience, we propose a 6Rs rule for sepsis and septic shock management: right patients, right time, right target, right antibiotics, right dose, and right source control. This rule encompasses rational decisions regarding the timing of treatment, the identification of the correct pathogen, the selection of appropriate antibiotics, the formulation of a scientifically based antibiotic dosage regimen, and the adequate control of infectious foci.@*CONCLUSIONS@#This review highlights how to recognize and treat sepsis and septic shock and provides rules and a standard flowchart for anti-infection therapy for sepsis and septic shock for use in the clinical setting.

Critical hemodynamic therapy oriented resuscitation helping reduce lung water production and improve survival / 中华医学杂志(英文版)

BACKGROUND@#Increased extravascular lung water (EVLW) in shock is common in the critically ill patients. This study aimed to explore the effect of cardiac output (CO) on EVLW and its relevant influence on prognosis.@*METHODS@#The hemodynamic data of 428 patients with pulse-indicated continuous CO catheterization from Department of Critical Care Medicine, Peking Union Medical College Hospital were retrospectively collected and analyzed. The patients were assigned to acute respiratory distress syndrome group, cardiogenic shock group, septic shock group, and combined shock (cardiogenic and septic) group according to their symptoms. Information on 28-day mortality and renal function was also collected.@*RESULTS@#The CO and EVLW index (EVLWI) in the cardiogenic and combined shock groups were lower than those in the other groups (acute respiratory distress syndrome group vs. cardiogenic shock group vs. septic shock group vs. combined shock group: CO, 5.1 [4.0, 6.2] vs. 4.7 [4.0, 5.7] vs. 5.5 [4.3, 6.7] vs. 4.6 [3.5, 5.7] at 0 to 24 h, P = 0.009; 4.6 [3.8, 5.6] vs. 4.8 [4.1, 5.7] vs. 5.3 [4.4, 6.5] vs. 4.5 [3.8, 5.3] at 24 to 48 h, P = 0.048; 4.5 [4.1, 5.4] vs. 4.8 [3.8, 5.5] vs. 5.3 [4.0, 6.4] vs. 4.0 [3.2, 5.4] at 48 to 72 h, P = 0.006; EVLWI, 11.4 [8.7, 19.1] vs. 7.9 [6.6, 10.0] vs. 8.8 [7.4, 11.0] vs. 8.2 [6.7, 11.3] at 0 to 24 h, P  0.05). In addition, there was no significant difference in tissue perfusion or renal function among the four groups during the observation period (P > 0.05). However, the cardiogenic shock group had a higher 28-day survival rate than the other three groups [log rank (Mantel-Cox) = 31.169, P < 0.001].@*CONCLUSION@#Tissue-aimed lower CO could reduce the EVLWI and achieve a better prognosis.

Vimentin modulates apoptosis and inflammatory cytokine release by a human monocytic cell line (THP-1) in response to lipopolysaccharides in vitro / 中华医学杂志(英文版)

BACKGROUND@#It has recently been recognized that serum vimentin is elevated in infectious diseases, and that vimentin plays a role in regulating neutrophils and macrophages associated inflammation. However, the mechanisms are unclear. This study was designed to explore the role of vimentin in regulating monocyte survival or apoptosis as well as inflammatory cytokine secretion in response to lipopolysaccharides (LPSs).@*METHODS@#A human monocytic leukemia cell line (THP-1) was transfected with vimentin-specific small interfering RNA (siRNA) or vimentin over-expressing plasmid. Apoptosis was assessed by TdT-mediated dUTP Nick-End Labeling (TUNEL) and DNA content assay. Immunoblotting was performed to detect apoptosis-associated proteins. Cytokines (interleukin [IL]-6, IL-10, and tumor necrosis factor α [TNF-α]) were measured by enzyme-linked immuno sorbent assay. Two-way analysis of variance followed by Student's t test was used to compare means between different groups.@*RESULTS@#Suppression of vimentin in THP-1 cells resulted in increased apoptotic response in the presence of LPS, while over-expression of vimentin could prevent the cells from apoptosis in response to LPS. LPS alone or suppression of vimentin resulted in significant up-regulation of caspase-3 (1.42 ± 0.20 of LPS alone and 1.68 ± 0.10 of vimentin suppression vs. control, t = 5.21 and 10.28, respectively, P < 0.05). In addition, pro-inflammatory cytokines (IL-6 and TNF-α) was significantly increased (IL-6: 577.90 ± 159.90 pg/day/10 cells vs. 283.80 ± 124.60 pg/day/10 cells of control, t = 14.76, P < 0.05; TNF-α: 54.10 ± 5.80 vs. 17.10 ± 0.10 pg/day/10 cells of control, t = 6.71, P < 0.05), while anti-inflammatory cytokine (IL-10) was significantly up-regulated in the THP-1 cells that over-expressed vimentin (140.9 ± 17.2 pg/day/10 cells vs. undetectable in control cells).@*CONCLUSIONS@#In summary, the vimentin may regulate innate immunity through modulating monocytes viability as well as inflammatory response in sepsis through shifting the balance of pro-inflammatory and anti-inflammatory cytokines.

Role of Combining Peripheral with Sublingual Perfusion on Evaluating Microcirculation and Predicting Prognosis in Patients with Septic Shock / 中华医学杂志(英文版)

<p><b>Background</b>Measurement of general microcirculation remains difficult in septic shock patients. The peripheral perfusion index (PI) and sublingual microcirculation monitoring are thought to be possible methods. This study was performed to determine whether assessing microcirculation by PI and a new parameter, proportion of perfusion vessel change rate (△PPV) from sublingual microcirculation monitoring, can be associated with patients' outcome.</p><p><b>Methods</b>A prospective observational study was carried out, including 74 patients with septic shock in a mixed intensive care unit. Systemic hemodynamic variables were obtained at T0 and 6 h after (T6). PI and sublingual microcirculation indicators were obtained using a bedside monitor and a sidestream dark-field device, respectively. The t-test, analysis of variance, Mann-Whitney U-test, Kruskal-Wallis test, receiver operating characteristic curve analysis with the Hanley-McNeil test, survival curves using the Kaplan-Meier method, and the log-rank (Mantel-Cox) test were used to statistical analysis.</p><p><b>Results</b>Systemic hemodynamics and microcirculation data were obtained and analyzed. Patients were divided into two groups based on whether the first 6 h lactate clearance (LC) was ≥20%; PI and △PPV were lower at T6 in the LC <20% group compared with LC ≥20% (PI: 1.52 [0.89, 1.98] vs. 0.79 [0.44, 1,81], Z = -2.514, P = 0.012; △PPV: 5.9 ± 15.2 vs. 17.9 ± 20.0, t = -2.914, P = 0.005). The cutoff values of PI and △PPV were 1.41% and 12.1%, respectively. The cutoff value of the combined indicators was 1.379 according to logistic regression. Area under the curve demonstrated 0.709 (P < 0.05), and the sensitivity and specificity of using combined indicators were 0.622 and 0.757, respectively. Based on the PI and △PPV cutoff, all the participants were divided into the following groups: (1) high PI and high △PPV group, (2) high PI and low △PPV group, (3) low PI and high △PPV group, and (4) low PI and low △PPV group. The highest Sequential Organ Failure Assessment score (14.5 ± 2.9) was in the low PI and low △PPV group (F = 13.7, P < 0.001). Post hoc tests showed significant differences in 28-day survival rates among these four groups (log rank [Mantel-Cox], 20.931; P < 0.05).</p><p><b>Conclusion</b>PI and △PPV in septic shock patients are related to 6 h LC, and combining these two parameters to assess microcirculation can predict organ dysfunction and 28-day mortality in patients with septic shock.</p>

Accelerated Autophagy of Cecal Ligation and Puncture-Induced Myocardial Dysfunction and Its Correlation with Mammalian Target of Rapamycin Pathway in Rats / 中华医学杂志(英文版)

<p><b>Background</b>Recent studies have indicated that autophagy is involved in sepsis-induced myocardial dysfunction. This study aimed to investigate the change of autophagy in cecal ligation and puncture (CLP)-induced myocardium dysfunction and its relationship with mammalian target of rapamycin (mTOR) pathway.</p><p><b>Methods</b>Totally, 12 rats were randomly divided into CLP group or sham-operated (SHAM) group. Cardiac tissues were harvested 18 h after CLP or sham operation. Pathology was detected by hematoxylin and eosin staining, cardiac functions by echocardiography, distribution of microtubule-associated protein light chain 3 type II (LC3II) by immunohistochemical staining, and autophagic vacuoles by transmission electron microscopy. Moreover, phosphorylation of mTOR (p-mTOR), phosphorylation of S6 kinase-1 (PS6K1), and LC3II and p62 expression were measured by western blotting. Pearson's correlation coefficient was used to analyze the correlation of two parameters.</p><p><b>Results</b>The results by pathology and echocardiography revealed that there was obvious myocardial injury in CLP rats (left ventricle ejection fraction: SHAM 0.76 ± 0.06 vs. CLP 0.59 ± 0.11, P < 0.01; fractional shortening: SHAM 0.51 ± 0.09 vs. CLP 0.37 ± 0.06, P < 0.05). We also found that the autophagy process was elevated by CLP, the ratio of LC3II/LC3I was increased (P < 0.05) while the expression of p62 was decreased (P < 0.05) in the CLP rats, and there were also more autophagosomes and autolysosomes in the CLP rats. Furthermore, the mTOR pathway in CLP myocardium was inhibited when compared with the sham-operated rats; p-mTOR (P < 0.01) and PS6K1 (P < 0.05) were both significantly suppressed following CLP challenge. Interestingly, we found that the mTOR pathway was closely correlated with the autophagy processes. In our study, while p-mTOR in the myocardium was significantly correlated with p62 (r = 0.66, P = 0.02), PS6K1 was significantly positively correlated with p62 (r = 0.70, P = 0.01) and negatively correlated with LC3II (r = -0.71, P = 0.01).</p><p><b>Conclusions</b>The autophagy process in the myocardium was accelerated in CLP rats, which was closely correlated with the inhibition of the mTOR pathway.</p>

Role of Triggering Receptor Expressed on Myeloid Cell-1 Expression in Mammalian Target of Rapamycin Modulation of CD8T-cell Differentiation during the Immune Response to Invasive Pulmonary Aspergillosis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Triggering receptor expressed on myeloid cell-1 (TREM-1) may play a vital role in mammalian target of rapamycin (mTOR) modulation of CD8+ T-cell differentiation through the transcription factors T-box expressed in T-cells and eomesodermin during the immune response to invasive pulmonary aspergillosis (IPA). This study aimed to investigate whether the mTOR signaling pathway modulates the proliferation and differentiation of CD8+ T-cells during the immune response to IPA and the role TREM-1 plays in this process.</p><p><b>METHODS</b>Cyclophosphamide (CTX) was injected intraperitoneally, and Aspergillus fumigatus spore suspension was inoculated intranasally to establish the immunosuppressed IPA mouse model. After inoculation, rapamycin (2 mg.kg-1.d-1) or interleukin (IL)-12 (5 μg/kg every other day) was given for 7 days. The number of CD8+ effector memory T-cells (Tem), expression of interferon (IFN)-γ, mTOR, and ribosomal protein S6 kinase (S6K), and the levels of IL-6, IL-10, galactomannan (GM), and soluble TREM-1 (sTREM-1) were measured.</p><p><b>RESULTS</b>Viable A. fumigatus was cultured from the lung tissue of the inoculated mice. Histological examination indicated greater inflammation, hemorrhage, and lung tissue injury in both IPA and CTX + IPA mice groups. The expression of mTOR and S6K was significantly increased in the CTX + IPA + IL-12 group compared with the control, IPA (P = 0.01; P= 0.001), and CTX + IPA (P = 0.034; P= 0.032) groups, but significantly decreased in the CTX + IPA + RAPA group (P < 0.001). Compared with the CTX + IPA group, the proportion of Tem, expression of IFN-γ, and the level of sTREM-1 were significantly higher after IL-12 treatment (P = 0.024, P= 0.032, and P= 0.017, respectively), and the opposite results were observed when the mTOR pathway was blocked by rapamycin (P < 0.001). Compared with the CTX + IPA and CTX + IPA + RAPA groups, IL-12 treatment increased IL-6 and downregulated IL-10 as well as GM, which strengthened the immune response to the IPA infection.</p><p><b>CONCLUSIONS</b>mTOR modulates CD8+ T-cell differentiation during the immune response to IPA. TREM-1 may play a vital role in signal transduction between mTOR and the downstream immune response.</p>

mTOR Modulates Lymphocyte Differentiation through T-bet and Eomesodermin in Response to Invasive Pulmonary Aspergillosis in Rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Aspergillosis infection is common in the patients with insufficient immunity. The role of mammalian target of rapamycin (mTOR), T-box expressed in T-cells (T-bet), and eomesodermin (EOMES) in mediating T lymphocytes differentiation in response to Aspergillus fumigatus infection in immunocompromised rats was investigated in this study.</p><p><b>METHODS</b>Invasive pulmonary aspergillosis (IPA) of immunosuppressive twenty male rats were established and sacrificed at 24 h (n = 5), 48 h (n = 5), 72 h (n = 5), and 96 h (n = 5) after A. fumigatus infection. In addition, control (n = 5), cyclophosphamide (CTX) (n = 5), and aspergillosis (n = 5) group were also established the tissues and pathology of lung tissue was examined by hematoxylin and eosin staining. CD8+ T-cells was sorted by flow cytometry. Serum mTOR, S6K, T-bet, and EOMES were quantified by enzyme-linked immunosorbent assay.</p><p><b>RESULTS</b>Histology of lung tissue indicated severe lung tissue injury including infiltration of inflammatory cells, alveolar wall damage or degradation, blood congestion, and hemorrhage in the CTX, IPA, and CTX + IPA rats. Hyphae were seen in the IPA, and CTX + IPA groups. The proportion of CD8+ T-cells was significantly increased in the animals of CTX + IPA. Memory CD8+ T-cells was significantly increased in early stage (24 h and 48 h, P < 0.001), but decreased in the late phase of fungal infection (72 h and 96 h) in the animals of CTX + IPA. In addition, at early stage of fungal infection (24 h and 48 h), serum mTOR (P < 0.001), S6K (P < 0.001), and T-bet (P < 0.05) was significantly higher, while EOMES was significantly lower (P < 0.001), in CTX + IPA group than that in control, CTX alone or IPA alone group. Conversely, serum mTOR, S6K, T-bet, and EOMES showed opposite changed in the late stage (72 h and 96 h). Pearson's correlation analysis indicated that mTOR and S6K were significantly correlated with T-bet (r = 0.901 and 0.91, respectively, P < 0.001), but negatively and significantly correlated with EOMES (r = -0.758 and -0.751, respectively, P < 0.001).</p><p><b>CONCLUSIONS</b>mTOR may regulate transcription factors of EOMES and T-bet, and by which mechanism, it may modulate lymphocytes differentiation in animals with immune suppression and fungal infection.</p>

Protective effects of hepatocyte growth factor on hypoxic human pulmonary microvascular endothelial cells / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the protective effects of hepatocyte growth factor (HGF) on hypoxic human pulmonary microvascular endothelial cells (HPMECs).</p><p><b>METHODS</b>HPMECs were cultured in vitro, and the hypoxic model was established by the physical method. Cells were divided into 4 groups: the control group, the hypoxic group, HGF group, and phytohemagglutinin (PHA) group. The 7(th) generation of HPMECs was evaluated by the method of immunocytochemistry. The persistence rate of HPMECs was measured by MTT assay and the adhesive cells were counted by the microscopy. The expression of intercellular adhesion molecule-1 (ICAM-1) protein was determined by immunofluorescence staining.</p><p><b>RESULTS</b>The adherence percentage of cells significantly decreased after hypoxia, whereas the expression of the ICAM-1 protein was significantly higher in the hypoxia group than in control group (P<0.01). Compared with the hypoxia group, the persistence and adherence percentage of cells in the HGF group significantly increased (P<0.01), whereas the expression of the ICAM-1 protein significantly dropped (P<0.01). In the PHA group, the persistence and adhesion rate were significantly different from those in the hypoxia group and HGF group (P<0.01), and the expression of the ICAM-1 protein increased significantly (P<0.01).</p><p><b>CONCLUSION</b>HGF could inhibit the hypoxic damage of HPMECs by decreasing the persistence and the adhesive capacity of these cells and inducing the expression of ICAM-1.</p>

Significance of low serum vitamin D for infection risk, disease severity and mortality in critically ill patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Hospitalized patients often have higher rate of vitamin D deficiency than healthy people. Vitamin D levels below normal are associated with hospital stay, increased incidence of adverse prognosis and increased mortality of a number of diseases. Whether there is a relationship between vitamin D levels and infection or sepsis in the critically ill is still unclear. This study will explore the relationship between vitamin D levels and risk of infection, assessment for disease severity, and predictor of mortality.</p><p><b>METHODS</b>To evaluate the value of vitamin D in intensive care unit (ICU) cases to sepsis, severity and prognosis assessment, high performance liquid chromatography and tandem mass spectrometry were used to measure the concentrations of vitamin D in sera of critically ill patients. The serum samples were drawn within the first 24 hours of ICU admission.</p><p><b>RESULTS</b>The study included 206 people, 50 healthy controls, 51 ICU control patients and 105 ICU diagnosed with sepsis. Critically ill ICU patients (ICU sepsis and ICU control group) had lower vitamin D concentration than normal people, but septic patients showed no significant reduction of vitamin D concentration when compared with critically ill patients with no positive etiological evidence. For assessment of disease severity, there were very low negative correlations between APACHE II, SAPS II and SOFA scores and vitamin D level. Additionally, patients of different 25-(OH)D levels showed no difference whether in terms of 28-day survival (X(2) = 1.78, P = 0.776) or 90-day survival (X(2) = 4.12, P = 0.389). Multivariate Logistic regression demonstrated that APECHE II and SAPS II scores were independent risk factors to deaths caused by sepsis.</p><p><b>CONCLUSION</b>Clinically, serum concentration of vitamin D is not an indicator for diagnosis and assessment in critically ill patients (ClinicalTrial.gov identifier NCT01636232).</p>

Genetic characterization of a Chinese family with familial idiopathic pulmonary fibrosis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease with an unknown cause. Recent studies have shown that genetic factors play an important role in the pathogenesis of IPF.</p><p><b>METHODS</b>To explore the genetic background of patients with IPF, a candidate gene approach was employed to screen for mutations in seven genes among members with familial IPF in mainland of China.</p><p><b>RESULTS</b>Within six of the candidate genes, a total of 31 point mutations were identified. Among the missense mutations, the SFTPA1 exon 6 CAG > AAG (Gln238Lys) and SFTPB exon 2 CAC > CCC (His2Pro) mutations caused changes in the physical and chemical properties of amino acids. Each sequence alteration was identified in sporadic IPF patients, control specimens (pneumonia patients and healthy persons). Genotype frequencies and allele frequencies of codon 238 in exon 6 of SFTPA1 were noted significantly higher in patients with IPF than those in other two control subjects. The computational protein structure prediction by protein homology modeling confirmed differences in three-dimensional structure between mutant SFTPA1 and original SFTPA1.</p><p><b>CONCLUSIONS</b>Although the functions of the mutant candidate genes vary, these genes may ultimately result in damage to alveolar epithelial cells, initiating the progress of pulmonary fibrosis. In particular, while pathophysiological mechanisms need to be illustrated, the Gln238Lys missense variant of exon 6 in the SFTPA1 may have potential susceptibility in the development of IPF, which was shown in patients with sporadic IPF with a statistically higher frequency.</p>