Angiotensin-converting enzyme 2 in severe acute respiratory syndrome coronavirus and SARS-CoV-2: A double-edged sword?

Human angiotensin-converting enzyme 2 (ACE2) facilitates cellular entry of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 as their common receptor. During infection, ACE2-expressing tissues become direct targets, resulting in serious pathological changes and progressive multiple organ failure or even death in severe cases. However, as an essential component of renin-angiotensin system (RAS), ACE2 confers protective effects in physiological circumstance, including maintaining cardiovascular homeostasis, fluid, and electrolyte balance. The absence of protective role of ACE2 leads to dysregulated RAS and thus acute changes under multiple pathological scenarios including SARS. This potentially shared mechanism may also be the molecular explanation for pathogenesis driven by SARS-CoV-2. We reasonably speculate several potential directions of clinical management including host-directed therapies aiming to restore dysregulated RAS caused by ACE2 deficiency. Enriched knowledge of ACE2 learned from SARS and COVID-19 outbreaks can provide, despite their inherent tragedy, informative clues for emerging pandemic preparedness.

Autophagy is required for the directed motility of keratinocytes driven by electric fields.

Endogenous wound electric fields (EFs), an important and fundamental occurrence of wound healing, profoundly influence the directed migration of keratinocytes. Although numerous studies have unveiled the signals responsible for EF-biased direction, the mechanisms by which EFs promote keratinocyte motility remains to be elucidated. In our study, EFs enhanced the directed migratory speed of keratinocytes by inducing autophagic activity, thereby facilitating skin barrier restoration. Initially, we found that electrical signals directed keratinocytes to the cathode with enhanced motility parameters [ i.e., trajectory distance, trajectory speed, displacement distance, and displacement speed ( Td/ t)] and more efficient migration (directionality and Td/ t along the x axis, among others). Meanwhile, EFs induced a time-dependent increase in autophagic activity in keratinocytes, with constant autophagic flux, accompanied by increased transcription of numerous autophagy-related genes. Deficiency in Atg5, a key protein necessary for autophagosome formation, led to significant reduction of autophagy, which was accompanied by a substantial reduction in EF-stimulated directed motility. These results demonstrated a causal relationship between autophagy and EF-directed migratory speed. In addition, both cell migration under normal conditions and EF-biased directionality were autophagy independent. Thus, our findings define autophagy as an important functional regulator of electrically enhanced directed motility, adding to a growing understanding of EFs.-Yan, T., Jiang, X., Lin, G., Tang, D., Zhang, J., Guo, X., Zhang, D., Zhang, Q., Jia, J., Huang, Y. Autophagy is required for the directed motility of keratinocytes driven by electric fields.

Obesity and severe coronavirus disease 2019: molecular mechanisms, paths forward, and therapeutic opportunities.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to have higher pathogenicity among patients with obesity. Obesity, termed as body mass index greater than 30 kg/m2, has now been demonstrated to be important comorbidity for disease severity during coronavirus disease 2019 (COVID-19) pandemic and associated with adverse events. Unraveling mechanisms behind this phenomenon can assist scientists, clinicians, and policymakers in responding appropriately to the COVID-19 pandemic. In this review, we systemically delineated the potential mechanistic links between obesity and worsening COVID-19 from altered physiology, underlying diseases, metabolism, immunity, cytokine storm, and thrombosis. Problematic ventilation caused by obesity and preexisting medical disorders exacerbate organ dysfunction for patients with obesity. Chronic metabolic disorders, including dyslipidemia, hyperglycemia, vitamin D deficiency, and polymorphisms of metabolism-related genes in obesity, probably aid SARS-CoV-2 intrusion and impair antiviral responses. Obesity-induced inadequate antiviral immunity (interferon, natural killer cells, invariant natural killer T cell, dendritic cell, T cells, B cell) at the early stage of SARS-CoV-2 infection leads to delayed viral elimination, increased viral load, and expedited viral mutation. Cytokine storm, with the defective antiviral immunity, probably contributes to tissue damage and pathological progression, resulting in severe symptoms and poor prognosis. The prothrombotic state, driven in large part by endothelial dysfunction, platelet hyperactivation, hypercoagulability, and impaired fibrinolysis in obesity, also increases the risk of severe COVID-19. These mechanisms in the susceptibility to severe condition also open the possibility for host-directed therapies in population with obesity. By bridging work done in these fields, researchers can gain a holistic view of the paths forward and therapeutic opportunities to break the vicious cycle of obesity and its devastating complications in the next emerging pandemic.

Epidemiological analysis of 9,779 burn patients in China: An eight-year retrospective study at a major burn center in southwest China.

Burns are tissue injuries caused by high temperature, chemicals or electricity. Severe burns may involve all of the organs and tissues of the human body, leading to a series of pathophysiological processes and even death. The present study reviewed the clinical data of burn patients, including cases of burn-associated death, to provide evidence for the strategy of burn prevention. Basic information from 13,205 inpatients treated between January 1, 2009 and December 31, 2016 was extracted from the database of the Institute of Burn Research at Southwest Hospital (Chongqing, China). After excluding 3,426 inpatients who were not primarily treated for burns, 9,779 patients remained; among them, 68 cases (0.7%) had died as a direct consequence of the burns. Based on baseline data, the mortality rate, total body surface area of the burn (TBSA), age, sex, cause of injury and complications were analysed. In general, males accounted for a higher percentage than female burn patients. Of the patients, 95.54% had a TBSA of <50%, and the rate of mortality of the patients was increased when the TBSA was ≥50%. The major causes of injury were scalds (41.60%), fire (26.92%) and electricity (15.29%), and the majority of victims were 14 years or younger. With improvements in burn treatment technology in recent years, burn patient mortality was significantly reduced. Complications, including multiple organ failure and severe systemic infection, may reduce the survival rate of patients. The major risk factors for death included burns resulting from explosions, as well as shock, age (aged 0-1 or ≥50 years), greater TBSA and full-thickness burn area. With increasing length of stay at the hospital, patient mortality decreased. The renewal of treatment concepts and refined patient management contributed to the shorter LOS and lower mortality in 2015 and 2016.

Pharmacological treatment of inhalation injury after nuclear or radiological incidents: The Chinese and German approach.

Inhalation injury is often associated with burns and significantly increases morbidity and mortality. The main toxic components of fire smoke are carbon monoxide, hydrogen cyanide, and irritants. In the case of an incident at a nuclear power plant or recycling facility associated with fire, smoke may also contain radioactive material. Medical treatments may vary in different countries, and in this paper, we discuss the similarities and differences in the treatments between China and Germany. Carbon monoxide poisoning is treated by 100% oxygen administration and, if available, hyperbaric oxygenation in China as well as in Germany. In addition, antidotes binding the cyanide ions and relieving the respiratory chain are important. Methemoglobin-forming agents (e.g., nitrites, dimethylaminophenol) or hydroxocobalamin (Vitamin B12) are options. The metabolic elimination of cyanide may be enhanced by sodium thiosulfate. In China, sodium nitrite with sodium thiosulfate is the most common combination. The use of dimethylaminophenol instead of sodium nitrite is typical for Germany, and hydroxocobalamin is considered the antidote of choice if available in cases of cyanide intoxications by fire smoke inhalation as it does not further reduce oxygen transport capacity. Systematic prophylactic use of corticosteroids to prevent toxic pulmonary edema is not recommended in China or Germany. Stable iodine is indicated in the case of radioiodine exposure and must be administered within several hours to be effective. The decorporation of metal radionuclides is possible with Ca (DTPA) or Prussian blue that should be given as soon as possible. These medications are used in both countries, but it seems that Ca (DTPA) is administered at lower dosages in China. Although the details of the treatment of inhalation injury and radionuclide(s) decorporation may vary, the general therapeutic strategy is very similar in China and Germany.

[Retrospective study on the myocardial damage of 252 patients with severe burn].

OBJECTIVE: To retrospectively analyze the risk factors and clinical manifestations of myocardial damage of patients with severe burn in order to provide evidence for its prevention and treatment. METHODS: Two hundred and fifty-two patients with severe burn admitted to 5 burn centers from January 2010 to June 2015, conforming to the study criteria, were treated in accordance with the fluid resuscitation formula of the Third Military Medical University. According to the creatine kinase isoenzyme-MB (CK-MB) level before treatment on admission, patients were divided into non-myocardial damage group (n=118, CK-MB level less than 75 U/mL) and myocardial damage group (n=134, CK-MB level higher than or equal to 75 U/mL). Data of patients in two groups were collected and evaluated such as gender, age, body mass, number of patients with chemical burn, admission time after injury, total burn area, full-thickness burn area, number of patients with inhalation injury, levels of haemoglobin, hematocrit, and blood lactate on admission and at post injury hour (PIH) 24 and 48, volumes of urine output and fluid input at PIH 24 and 48, levels of creatinine, urea nitrogen, total bile acid, diamine oxidase on admission and at PIH 24 and 48, and mortality. Furthermore, patients were divided into three groups, i. e. less than 50% total body surface area (TBSA) group (n=110), larger than or equal to 50% TBSA and less than 80% TBSA group (n=83), and larger than or equal to 80% TBSA group (n=59) according to the total burn area, and the incidence rates of myocardial damage in patients of three groups were recorded. Data were processed with chi-square test, t test, Wilcoxon test, analysis of variance for repeated measurement, and the values of P were adjusted by Bonferroni. Basic data of 252 patients were processed with binary logistic regression analysis. Receiver operating characteristic curve of total burn area of 252 patients was drawn to predict myocardial damage. RESULTS: (1) There were no statistically significant differences in age, body mass, number of patients with chemical burn, number of patients with inhalation injury, and full-thickness burn area between two groups (with t values respectively 0.20 and 0.31, χ(2) values respectively 0.49 and 4.10, Z=1.42, P values above 0.05). There were statistically significant differences in gender, admission time after injury, and total burn area of patients between two groups (χ(2)=5.00, with t values respectively 2.44 and 3.13, P<0.05 or P<0.01). (2) Gender, admission time after injury, and total burn area were independent risk factors related to myocardial damage in the patients (with odds ratios respectively 2.608, 3.620, and 1.030; 95% confidence intervals respectively 1.315-5.175, 1.916-6.839, and 1.011-1.049; P values below 0.01). (3) The incidence rates of myocardial damage of patients in less than 50% TBSA group, larger than or equal to 50% TBSA and less than 80% TBSA group, and larger than or equal to 80% TBSA group were 38.2% (42/110), 54.2% (45/83), and 61.0% (36/59) respectively, and there was statistically significant difference among them (χ(2)=9.46, P<0.05). (4) The total area under receiver operating characteristic curve of total burn area to predict myocardial damage of 252 patients was 0.706 (with 95% confidence interval 0.641-0.772, P<0.01), and 51.5% TBSA was chosen as the optimal threshold value, with sensitivity of 62.6% and specificity of 65.3%. (5) Compared with those in non-myocardial damage group, except the levels of haemoglobin and hematocrit at PIH 48 (with t values respectively -0.76 and -0.61, P values above 0.05), the levels of haemoglobin, hematocrit, and blood lactate of patients in myocardial damage group were significantly increased at each time point (with t values from -2.80 to -2.06, P<0.05 or P<0.01). Compared with those in non-myocardial damage group, the volume of urine output of patients was significantly declined (with t values respectively 2.05 and 3.68, P<0.05 or P<0.01), while the volume of fluid input of patients was not obviously changed in myocardial damage group at PIH 24 and 48 (with t values respectively 1.01 and 1.08, P values above 0.05). (6) Compared with those in non-myocardial damage group, the level of creatinine of patients was significantly increased on admission and at PIH 24 and 48 (with Z values from -2.91 to -1.99, P<0.05 or P<0.01), the level of urea nitrogen of patients was only significantly increased at PIH 24 and 48 (with t values respectively -4.75 and -5.24, P values below 0.01), the level of total bile acid of patients was not obviously changed on admission and at PIH 24 and 48 (with t values from -0.81 to -0.20, P values above 0.05), and the level of diamine oxidase of patients was only significantly increased on admission and PIH 24 in myocardial damage group (with t values respectively -3.97 and -2.02, P<0.05 or P<0.01). (7) Compared with that in myocardial damage group, the mortality of patients in non-myocardial damage group was significantly declined (χ(2)=5.81, P<0.05). CONCLUSIONS: Patients with severe burn have high incidence of myocardial damage, which may be predicted by total burn area. Severely burned patients with myocardial damage are more likely to suffer from decline of effective circulating volume, tissue oxygenation disorders, and damage in other organs in shock stage.

The effects of different hyperbaric oxygen manipulations in rats after traumatic brain injury.

The protective effects of hyperbaric oxygenation following traumatic brain injury have been widely investigated; however, few studies have made systematic comparisons between the different hyperbaric oxygenation manipulations and their corresponding effects. In this study, male Sprague-Dawley rats were observed at 4h, 15d and 75d after traumatic brain injury. The effects of the different hyperbaric oxygenation manipulations on the rats were compared based on morphological, molecular biological and behavioral tests. Our results showed that hyperbaric oxygenation inhibited cell apoptosis in the rat hippocampus and improved their physiological functions. The effects observed in the hyperbaric oxygen-early group were better than the hyperbaric oxygen-delayed group, and the hyperbaric oxygen-early-delayed group demonstrated the best effects among all the groups. Our results showed the hyperbaric oxygenation was recommended early and delayed post-traumatic brain injury and exposure to hyperbaric oxygenation should be prolonged. These findings provide new ideal therapeutic insight for the clinical treatment of traumatic brain injury.

Spinal changes of a newly isolated neuropeptide endomorphin-2 concomitant with vincristine-induced allodynia.

Chemotherapy-induced neuropathic pain (CNP) is the major dose-limiting factor in cancer chemotherapy. However, the neural mechanisms underlying CNP remain unclear. There is increasing evidence implicating the involvement of spinal endomorphin-2 (EM2) in neuropathic pain. In this study, we used a vincristine-evoked rat CNP model displaying mechanical allodynia and central sensitization, and observed a significant decrease in the expression of spinal EM2 in CNP. Also, while intrathecal administration of exogenous EM2 attenuated allodynia and central sensitization, the mu-opioid receptor antagonist ß-funaltrexamine facilitated these events. We found that the reduction in spinal EM2 was mediated by increased activity of dipeptidylpeptidase IV, possibly as a consequence of chemotherapy-induced oxidative stress. Taken together, our findings suggest that a decrease in spinal EM2 expression causes the loss of endogenous analgesia and leads to enhanced pain sensation in CNP.

[Influence of age on median lethal burn area of burn patients].

OBJECTIVE: To discuss the influence of age on the LA50 (the burn area lethal to 50% of patients) of burn patients. METHODS: (1) Twenty-three thousand and seventy-three burn patients hospitalized in our center from December 1958 to December 2004 were enrolled, and they were divided into 25 age groups. LA50 values of total and full-thickness burn areas of patients in each age group were computed with probit regression method with Probit analysis of SPSS 11.0. (2) Those age groups with similar LA50 values were merged into one age group; thus 4 new age groups were formed. LA50 and its 95% confidence interval (CI) of total and full-thickness burn areas of patients in each age group were computed respectively. (3) All the patients were divided into group A (admitted from 1 December 1958 to 31 December 1983) and group B (admitted from 1 January 1984 to 31 December 2004) according to the admission time. LA50 and its 95% CI of total and full-thickness burn areas of patients in each age group of groups A and B were computed respectively. RESULTS: (1) LA50 values of total and full-thickness burn areas of patients among the 25 age groups were low in age groups younger than or equal to 5 years, which increased in age groups older than 5 years, distinctly higher in age groups older than 15 years, and they became lower in age groups older than 60 years. (2) LA50 values of total and full-thickness burn areas of patients in the 4 merged age groups were lowest in age groups older than 60 years (50.90% TBSA) and younger than or equal to 5 years (35.81% TBSA), and highest in age group older than 15 years and younger than or equal to 60 years (89.38% and 59.22% TBSA). There were statistically significant differences in LA50 of total and full-thickness burn areas of patients among 4 merged age groups [with 95% CI values of LA50 of total burn areas of patients in age groups ranging from young to old respectively (56.87 to 64.69)%, (64.46 to 74.36)%, (85.89 to 93.37)%, (44.55 to 60.73)% TBSA; with 95% CI values of LA50 of full-thickness burn areas of patients in age groups from young to old respectively (32.67 to 39.69)%, (40.86 to 50.41)%, (55.27 to 63.85)%, (32.46 to 54.86)% TBSA]. (3) LA50 values of total and full-thickness burn areas of patients in group B (98.94% and 73.23% TBSA) were significantly higher than those in group A (69.61% and 39.79% TBSA). There were differences in LA50 values of patients among different age groups in both group A and group B. The variation trend of LA50 values of patients among the 4 age groups in groups A and B was almost the same. Except for LA50 of total burn areas of patients in age group older than 5 years and younger than or equal to 15 years and LA50 of full-thickness burn areas of patients in age group older than 60 years, there were statistically significant differences in the LA50 of total and full-thickness burn areas of the other patients between group A and group B [with 95% CI of LA50 of total burn areas of patients of younger than or equal to 5 years, older than 15 years and younger than or equal to 60 years, and older than 60 years respectively (48.38 to 56.07)% and (68.68 to 81.35)% TBSA, (75.91 to 84.89)% and (97.09 to 110.45)% TBSA, (30.08 to 45.08)% and (60.67 to 102.69)% TBSA; with 95% CI of LA50 of full-thickness burn areas of patients of younger than or equal to 5 years, older than 5 years and younger than or equal to 15 years, older than 15 years and younger than or equal to 60 years respectively (27.48 to 34.69)% and (42.09 to 54.03)% TBSA, (34.78 to 46.43)% and (49.62 to 69.47)% TBSA, (43.98 to 51.77)% and (66.43 to 77.99)% TBSA]. CONCLUSIONS: Age is one of the important factors that influence the LA50 of burn patients. LA50 in different age groups increases with the development of medical technology; however, the influence of age on LA50 is not visibly changed by the advance of treatment.

[Evaluation of allogenic complement-regulating proteins in the peripheral blood cells of chimeric rat models harboring human cord blood stem cells].

OBJECTIVE: To analyze the mechanisms of surrogate tolerogenesis induced by chimeric donors. METHODS: Hematopoietic stem cells (HSCs) from human cord blood were transplanted into fetal rats via intrauterine injection and infused into the liver of the neonatal rats to establish chimeric rat models with human HSCs. Four weeks after birth, flow cytometry was performed to analyze the percentages of human CD45 (hCD45), CD55 (hCD55) and CD59 (hCD59)-positive cells in the peripheral blood cells of the chimeric rats. The distributions of hCD55- and hCD59-positive cells in different hCD45/SSC gating regions were observed. The resistance of the peripheral blood lymphocytes to complements-mediated cytolysis was assessed by complement-dependent cytotoxicity (CDC) test in the chimeric rats and compared with that in control rats. The correlation between CDC and the human complement-regulating proteins in the chimeric rats were analyzed statistically. RESULTS: On hCD45/SSC gating, the percentages of hCD55- and hCD59-positive cells in hCD45-positives region were (53.69-/+18.23)% and (31.8-/+27.5)%, accounting for (2.0-/+1.32)% and (0.76-/+0.56)% of the total cell population, respectively, which were significantly lower than the cell percentages in the extensive region (t=2.71, P=0.043 and t=3.64, P=0.015). The cytolytic rate of PBLs incubated with normal human serum was (22.32-/+15.10)% in the chimeric rats, significantly lower than that in the non-chimeric rats [(60.7-/+22.65)%, t=4.16, P<0.001). In the chimeric rats, hCD55-positive cell percentage was inversely correlated in the peripheral blood karyocytes the cytolysis rate in CDC (r=-0.679, P=0.031), and positively correlated to hCD45-positive cell percentage (r=0.658, P=0.038). CONCLUSION: The hCD45-positives region is the cluster of chimeric human cells expressing human complement-regulating proteins. The peripheral blood lymphocytes from chimeric donor can resist the cytolysis mediated by human complement. The presence of allogenic CD55 and CD59 antigens in chimeric donors may be the basis of surrogate tolerogenesis for xenotransplantation.

[Preliminary study on immunologic tolerance for hetero-skin graft induced by chimeric donors].

OBJECTIVE: To explore the feasibility of transplanting the skin from chimeric rats to rabbits. METHODS: Chimeric rats were produced by transplanting the haematopoietic stem cells (HSCs) from rabbit marrows into fetal rats in uterus and followed by injecting the HSCs into the livers of the rats at newborn stage. After six weeks, the skin from chimeric rats was transplanted to the rabbits. In group A, the skin grafts from chimeric rat donors were transplanted to the HSCs donating rabbits, with the skin from non-chimeric rat to normal rabbits were used as control. In group B, the skin grafts from chimeric and non-chimeric rats were transplanted to the HSCs donating rabbits at the same time. Gross observation and the surviving time of heterogenic-skin graft were observed. The wound healing time was also recorded. RESULTS: In group A, the surviving time and the wound healing time of non-chimeric grafts were (9.3 +/- 1.8) days and (20.9 +/- 2.1) days, respectively, while those in chimeric grafts were (15.1 +/- 2.6) and (18.5 +/-1.3) days, respectively. In group B, the surviving time and the wound healing time of non-chimeric grafts were similar to those of group A. Compared with those in non-chimeric grafts, the surviving time of chimeric grafts in both groups were prolonged (P < 0.01), and the wound healing time shortened (P < 0.05 or 0.01). Most of the wounds healed quickly after rejection of chimeric grafts, while the wounds with non-chimeric grafts were re-opened with exudation and some necrotic tissue. CONCLUSION: Immunologic tolerance for skin graft can be induced by the skin from chimeric donors, which can prolong the surviving time of skin grafts and shorten the wound healing time.

[Categorization of burn severity].

OBJECTIVE: To seek a new method for the categorization of burn severity. METHODS: Burn patients hospitalized in our center from December of 1958 to December of 2004 were enrolled in the study, and they were divided into different age groups according to same mortality, then the patients in each group were subdivided into 4 groups according to the burn severity: i.e., mild burns, moderate burns, severe burns, serious severe burns. The total burn area, the number of cases, the mortality, and the area of DI degree burns were statistically analyzed in each subgroup, and the scope in total burn area and area of III degree burns were taken as standards to define the degree of burns. The logistic regression equation was established with probability of death as the variable, and age, total burn area, burn area of different degrees as concomitant variables to form a logistic regression formula. It was used to predict the probability of death of patients hospitalized in 2005, 50 as to check whether the corresponding indices of these patients were consistant with above standard of categorization into degrees, and to judge hum severity of the patients who had concomitant inhalation injury, severe associated injury, or those with serious disease before burns. RESULTS: The patients were divided into three groups: less than 2 years of age (including 2 years of age), 2 to 55 years of age(including 55 years of age), and older than 55 years of age groups. The classification standard of burn area was shown in table 2 of the article. The probability of death and corresponding indices predicted hy the logistic regression equation were highly coincident with our standard. Patients with moderate inhalation injury could be regarded as patients with severe or most severe burns, while severity of those with mild inhalation injury could be determined by burn area alone. CONCLUSION: The logistic regression equation is a good method to predict the severity of burn patients, with reasonable age specificity grouping, and accurate and practical scoring of division for corresponding burn severity.