Structure of SARS-CoV-2 and treatment of COVID-19 / 生理学报

Corona virus disease 2019 (COVID-19) is a new type of coronavirus pneumonia, which is caused by infection of a novel coronavirus, SARS-CoV-2. The virus infects lung cells by binding angiotensin-converting enzyme 2 (ACE2) of cell surface, which leads to leukocyte infiltration, increased permeability of blood vessels and alveolar walls, and decreased surfactant in the lung, causing respiratory symptoms. The aggravation of local inflammation causes cytokine storm, resulting in systemic inflammatory response syndrome. In December 2019, a number of new pneumonia cases were reported by Wuhan Municipal Health Commission, after then a novel coronavirus was isolated and identified as SARS-CoV-2. To the date of Sep. 13th, 2020, COVID-19 is affecting 216 countries or regions, causing 28 637 952 cases, 917 417 deaths, and the mortality rate is 3.20%. This review will summarize the structure of SARS-CoV-2 and the pharmaceutical treatment of COVID-19, and their potential relationships.

Ferroptosis in respiratory diseases / 生理学报

Ferroptosis is a novel form of regulated cell death which is dependent on iron and reactive oxygen species (ROS) and associated with the accumulation of lipid peroxides. It is obviously different from other cell death types in terms of morphology, biochemistry, genetics, etc. Also, it is related to the production of iron catalyzed lipid peroxides which is triggered by non-enzymatic or enzymatic reactions. Ferroptosis has been proved to be involved in hematological diseases, cardio-cerebrovascular diseases, liver and kidney diseases. This paper will review the definition, mechanism, inducers of ferroptosis, as well as the function of ferroptosis in respiratory system. We expect to present a new concept for respiratory research and suggest potential targets for clinical prevention and treatment of respiratory diseases.

Adenoid cystic carcinoma of trachea: a case report and review of literature / 中华医学杂志(英文版)

Primary tracheal tumors are relatively rare. Here we report one case of primary adenoid cystic carcinoma of the trachea which was ever misdiagnosed as asthma and hysteria. In this case, the pulmonary function test was normal, and firstly no obvious abnormalities were found in laryngoscopy, bronchoscopy and CT scan of chest. Later a sagittal and coronal reconstruction CT scan of trachea showed a mass situated in the subglottic trachea. Lastly a laryngoscopy was again done after a tracheal incision and showed a small mass in the posterior wall of the subglottic trachea, and tumor ablation was performed. In addition, we reviewed the literature of primary tracheal tumors and summarized the epidemiology, presenting features, available therapeutic options of the disease.

Efficacy and significance of various scores for pneumonia severity in the management of patients with community-acquired pneumonia in China / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Community-acquired pneumonia (CAP) remains one of the leading causes of death from infectious diseases around the world. Most severe CAP patients are admitted to the intensive care unit (ICU), and receive intense treatment. The present study aimed to evaluate the role of the pneumonia severity index (PSI), CURB-65, and sepsis score in the management of hospitalized CAP patients and explore the effect of ICU treatment on prognosis of severe cases.</p><p><b>METHODS</b>A total of 675 CAP patients hospitalized in the Second Affiliated Hospital of Zhejiang University School of Medicine were retrospectively investigated. The ability of different pneumonia severity scores to predict mortality was compared for effectiveness, while the risk factors associated with 30-day mortality rates and hospital length of stay (LOS) were evaluated. The effect of ICU treatment on the outcomes of severe CAP patients was also investigated.</p><p><b>RESULTS</b>All three scoring systems revealed that the mortality associated with the low-risk or intermediate-risk group was significantly lower than with the high-risk group. As the risk level increased, the frequency of ICU admission rose in tandem and LOS in the hospital was prolonged. The areas under the receiver operating characteristic curve in the prediction of mortality were 0.94, 0.91 and 0.89 for the PSI, CURB-65 and sepsis score, respectively. Compared with the corresponding control groups, the mortality was markedly increased in patients with a history of smoking, prior admission to ICU, respiratory failure, or co-morbidity of heart disease. The differences were also identified in LOS between control groups and patients with ICU treatment, heart, or cerebrovascular disease. Logistic regression analysis showed that age over 65 years, a history of smoking, and respiratory failure were closely related to mortality in the overall CAP cohort, whereas age, ICU admission, respiratory failure, and LOS at home between disease attack and hospital admission were identified as independent risk factors for mortality in the high-risk CAP sub-group. The 30-day mortality of patients who underwent ICU treatment on admission was also higher than for non-ICU treatment, but much lower than for those patients who took ICU treatment subsequent to the failure of non-ICU treatment.</p><p><b>CONCLUSIONS</b>Each severity score system, CURB-65, sepsis severity score and especially PSI, was capable of effectively predicting CAP mortality. Delayed ICU admission was related to higher mortality rates in severe CAP patients.</p>

Airborne fine particulate matter induced pulmonary inflammation as well as oxidative stress in neonate rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Airborne fine particulate matter (PM) can induce pulmonary inflammation which may adversely affect human health, but very few reports about its effect on the neonate rats are available. This study aimed to observe the potential impact and toxicity of fine PMs on the airway in neonate rats.</p><p><b>METHODS</b>Pulmonary inflammation, cytotoxicity, histopathology, and antioxidants as well as oxidant products were assessed 24 hours after intratracheal instillation of fine PM consecutively for 3 days. Cytotoxicity of fine PM was measured in HEp-2 cells.</p><p><b>RESULTS</b>Rats treated with high dose fine PM developed significant pulmonary inflammation characterized by neutrophil and macrophage infiltration. The inflammatory process was related to elevated level of TNF-α and prooxidant/antioxidant imbalance in the lung. Cytotoxicity studies performed in human epithelial cells indicated that high dose fine PM significantly reduced cell viability.</p><p><b>CONCLUSION</b>The study demonstrated acute exposure to fine PM induced airway inflammation as well as increased oxidative stress in addition to its direct toxic effect on airway epithelium cells.</p>

Aerodynamics study on pressure changes inside pressure-type whole-body plethysmograph produced by flowing air / 生理学报

When using pressure-type plethysmography to test lung function of rodents, calculation of lung volume is always based on Boyle's law. The precondition of Boyle's law is that perfect air is static. However, air in the chamber is flowing continuously when a rodent breathes inside the chamber. Therefore, Boyle's law, a principle of air statics, may not be appropriate for measuring pressure changes of flowing air. In this study, we deduced equations for pressure changes inside pressure-type plethysmograph and then designed three experiments to testify the theoretic deduction. The results of theoretic deduction indicated that increased pressure was generated from two sources: one was based on Boyle's law, and the other was based on the law of conservation of momentum. In the first experiment, after injecting 0.1 mL, 0.2 mL, 0.4 mL of air into the plethysmograph, the pressure inside the chamber increased sharply to a peak value, then promptly decreased to horizontal pressure. Peak values were significantly higher than the horizontal values (P<0.001). This observation revealed that flowing air made an extra effect on air pressure in the plethysmograph. In the second experiment, the same volume of air was injected into the plethysmograph at different frequencies (0, 0.5, 1, 2, 3 Hz) and pressure changes inside were measured. The results showed that, with increasing frequencies, the pressure changes in the chamber became significantly higher (P<0.001). In the third experiment, small animal ventilator and pipette were used to make two types of airflow with different functions of time. The pressure changes produced by the ventilator were significantly greater than those produced by the pipette (P<0.001). Based on the data obtained, we draw the conclusion that, the flow of air plays a role in pressure changes inside the plethysmograph, and the faster the airflow is, the higher the pressure changes reach. Furthermore, the type of airflow also influences the pressure changes.

Relationship between measurements of tidal volume and thoracic inflating volume by pressure plethysmography in mice / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To evaluate the accordance of tidal volume (TV) with thoracic inflating volume (TIV) measured by pressure whole-body or double-chamber plethysmography in mice.</p><p><b>METHODS</b>TV and TIV by double-chamber plethysmography were simultaneously measured in 6 mice with spontaneous respiratory frequencies 90 - 120/min; TV and TIV by whole-body plethysmography were measured in 8 paralyzed mice ventilated by fixed frequency.</p><p><b>RESULT</b>TIV value by double-chamber plethysmography was significantly higher than TV [(0.369 +/- 0.014) ml vs (0.356 +/- 0.012) ml, P < 0.01)] in 6 spontaneously breathing mice. TIV value by whole-body plethysmography was significantly lower than TV[(0.233 +/- 0.003) ml vs 0.3 ml, P < 0.001] in 8 paralyzed mice.</p><p><b>CONCLUSION</b>The TV value assessed by TIV measurement can not be accurate, because of the humidifying and heating of inhaled air and negative thoracic pressure during the measurement.</p>

Validity of Asthma Control Test in Chinese patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>So far, in China, there has been no effective or easy procedure to define the control of asthma. This study assesses the validity of Asthma Control Test in Chinese patients.</p><p><b>METHODS</b>Three questionnaires (Asthma Control Test, Asthma Control Questionnaire and the 30 second asthma test) were administered to 305 asthma patients from 10 teaching hospitals across China. Spirometry was also used. Asthma specialists rated the control of asthma according to patients' symptoms, medications and forced expiratory volume in first second. The patients were divided into noncontrolled group and controlled group according to the specialists' rating. Reliability, empirical validity and screening accuracy were conducted for Asthma Control Test scores. Screening accuracy was compared among 3 questionnaires. The patients' self rating and the specialists' rating were also compared.</p><p><b>RESULTS</b>The internal consistency reliability of the 5-item Asthma Control Test was 0.854. The correlation coefficient between Asthma Control Test and the specialists' rating was 0.729, which was higher than other instruments. Asthma Control Test scores discriminated between groups of patients differing in the percent predicted forced expiratory volume in first second (F = 26.06, P < 0.0001), the specialists' rating of asthma control (F = 88.24, P < 0.0001) and the Asthma Control Questionnaire scores (F = 250.57, P < 0.0001). Asthma Control Test showed no significant difference with Asthma Control Questionnaire in the percent correctly classified, while the percent correctly classified by Asthma Control Test was much higher than 30 second asthma test. The patients' self rating was the same as assessment of the specialists (t = 0.65, P = 0.516).</p><p><b>CONCLUSION</b>The Asthma Control Test is an effective and practicable method for assessing asthma control in China.</p>

Effect of cigarette smoke extract on lipopolysaccha-ride-activated mitogen-activated protein kinase signal transduction pathway in cultured cells / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Lipopolysaccharide (LPS) forms outer membrane of the wall of Gram-negative cells. LPS can directly cause damage to epithelia of respiratory tract and is the major factor responsible for the chronic inflammation of respiratory passage. The mitogen-activated protein kinase (MAPK) signal transduction pathway of the airway epithelia is intimately associated with the action of LPS. The chronic inflammation of respiratory tract and smoking are interrelated and entwined in the development and progression of chronic lung diseases. This study was designed to examine the effects of cigarette smoke extract (CSE) and LPS on MAPK signal transduction pathway in order to further understand the roles CSE and LPS play in chronic lung inflammation.</p><p><b>METHODS</b>Cultured primary human epithelial cells of airway were divided into four groups according to the stimulants used: blank control group, LPS-stimulation group, CSE-stimulation group and CSE plus LPS group. Western blotting was employed for the detection of phosphorylation level of extracellular-signal-regulated-kinase (ERK(1/2)), p38 MAPK and c-Jun N-terminal kinase (JNK). The expression of cytokines of MAPK transduction pathway (granulocyte-macrophage colony stimulating factor (GM-CSF) and mRNA of IL-8) in the primary epithelial cells of respiratory tract was also determined.</p><p><b>RESULTS</b>Western blotting revealed that the phosphorylation levels of ERK(1/2), p38 MAPK and JNK were low and 2 hours after the LPS stimulation, the phosphorylation of ERK(1/2), p38 MAPK and JNK were all increased. There was a significant difference in the phosphorylation between the LPS-stimulation group and blank control group (P < 0.05); no significant difference was found between CSE-stimulation group and blank control group (P > 0.05); there was a significant difference between CSE + LPS group and blank control group and between CSE + LPS group and LPS group (P < 0.05). The phosphorylation of CSE-LPS group was higher than that of blank control group but lower than that of LPS group. In blank control group, the expression of IL-8 and GM-CSF mRNA was low in the epithelial cells of airway and the release of IL-8 and GM-CSF was also at a low level. One hour after LPS stimulation, the level of IL-8 mRNA increased (P < 0.05) and reached a peak after 2 hours. On the other hand, GM-CSF mRNA level increased 2 hours after the stimulation (P < 0.05) and reached the highest level 4 hours after the stimulation. Two hours after LPS stimulation, IL-8 and GM-CSF protein level began to rise (P < 0.05), and the level was the highest 8 hours after the stimulation (P < 0.01). Stimulation with CSE alone had no effect on the release of IL-8 and GM-CSF and expression of IL-8 mRNA (P > 0.05), but pre-treatment with CSE could delay the LPS-induced release of IL-8 and GM-CSF and the expression of IL-8 mRNA and its peak was lower.</p><p><b>CONCLUSIONS</b>LPS stimulation can significantly increase the phosphorylation of ERK(1/2), p38 MAPK and JNK in the epithelial cells of airway and activate the MAPK transduction pathway, thereby can activate the downstream signal transduction pathway, and can ultimately result in the release of cytokines by the epithelial cells of airway. CSE can partially abolish the LPS-induced activation of MAPK signal transduction pathway and the expression of cytokines of the pathway, which might contribute to the development and progression of the inflammatory reactions in COPD patients.</p>

Effect of respiratory syncytial virus on the activity of matrix metalloproteinase in mice / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Respiratory syncytial virus (RSV) is a common pathogen in the lower respiratory tract of infants and children. Recent studies have shown that in adults, especially in the elderly population who have relatively weak immunity, lower respiratory tract infection is not uncommon. RSV was detected in 22% hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (COPD), and the detection rate was only next to that of parvovirus and influenza virus respectively. Further studies revealed that lung infection of RSV could lead to inflammatory destruction and structural remodeling. This study was undertaken to examine the effect of infection with RSV on matrix metalloproteinase (MMPs) in mice, and to explore the role of RSV in the pathogenesis of pulmonary diseases.</p><p><b>METHODS</b>Twenty BALB/c mice were divided randomly into an RSV infection group and a blank control group. The mice in the RSV infection group were given 100 microl liquid containing 10(6) PFU of RSV by intranasal instillation. Three days after the infection, the bronchoalveolar lavage fluid (BALF) was harvested and RT-PCR and Western blotting were used to detect MMP-9 and the expression of tissue inhibitors of matrix metalloproteinase (TIMP)-1 mRNA in lung tissues. Gelatin zymography was employed to detect the activities of MMP-9 and MMP-2 in BALF. Immunohistochemistry was used to determine the expressions of E-cadherin (E-cd) and proliferating cell nuclear antigen (PCNA) in the lung tissues.</p><p><b>RESULTS</b>In the BALF of the mice infected with RSV, the activities of MMP-9 and MMP-2 were significantly increased (t = 6.08, P < 0.01 and t = 5.68, P < 0.01). The levels of mRNA and proteins of MMP-9 in the lung tissues of the mice infected with RSV were significantly elevated, and the mRNA and protein levels were significantly higher than those of the blank controls. Though the ratio of MMP-9/TIMP-1 mRNA in the lung tissues of the infected mice was not significantly different from that of the normal controls, the ratio of the MMP-9/TIMP-1 protein in the RSV infection group was significantly higher than that in the control group. Moreover, the number of cells with positive E-cd expression was decreased and the number of cells positive for PCNA was increased, with an enhanced expression.</p><p><b>CONCLUSIONS</b>In mice, infection with RSV can significantly increase the activities of MMP-9 and MMP-2, and conspicuously elevate the mRNA transcription of MMP-9. RSV infection can increase the activity of gelatinase while up-regulating its inhibitory factors but increase its protein ratio of MMP-9/TIMP-1 in lung tissues, thereby facilitating fibrosis after structural destruction of the airway. The resultant status might be an important factor causing chronic reconstruction of the airway.</p>

A case of chylothorax treated curatively with Sapylin, a streptococcus preparation / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Chylothorax is an uncommon disease where fatty fluid accumulates within the chest cavity. Conservative management, including repeated thoracentesis or pleurodesis, seems to be suitable to most cases. Herein, we present a case of efficacious pleurodesis by intrapleural injection of Sapylin, a streptococcus preparation, for the treatment of chylothorax. A 52-year-old non-smoking female farmer was diagnosed as idiopathic chylothorax after we ruled out possible causes including chest trauma, lymphoma, lung cancer, filariasis, tuberculosis, and etc. Two-time intra-thoracic injection of 3 Klinische Einheit (KE) Sapylin achieved rapid and effective control of chylothorax with no severe side effects. Sapylin may facilitate pleurodesis by producing a strong inflammatory response.

CD69 expression on airway eosinophils and airway inflammation in a murine model of asthma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Asthma is a chronic airway disease with inflammation characterized by physiological changes (airway hyper-responsiveness, AHR) and pathological changes (inflammatory cells infiltration and mucus production). Eosinophils play a key role in the allergic inflammation. But the causative relationship between eosinophils and airway inflammation is hard to prove. One of the reasons is lack of activation marker of murine eosinophils. We investigated the expression of CD69 on murine eosinophils in vitro, the relationship between the expression of CD69 on eosinophils from peripheral blood and bronchoalveolar lavage fluid and on airway inflammation in asthmatic mice.</p><p><b>METHODS</b>Eosinophils from peripheral blood of IL-5 transgenic mice (NJ.1638) were purified. Mice were divided into five groups: wild type mice sensitized and challenged with saline (WS group), wild type mice sensitized and challenged with ovalbumin (WO group), IL-5(-/-) mice sensitized and challenged with saline and transferred with purified eosinophils (ISE group), IL-5(-/-) mice sensitized and challenged with OVA and transferred with purified eosinophils (IOE group), IL-5(-/-) mice sensitized and challenged with OVA and transferred with purified eosinophils, pretreated with anti CD4 monoclonal antibody (IOE+antiCD4mAb group). IL-5(-/-) mice were sensitized with OVA at day 0 and day 14, then challenged with OVA aerosol. On days 24, 25, 26 and 27 purified eosinophils were transferred intratracheally to IL-5(-/-) mice. On day 28, blood and BALF were collected and CD69 expression on eosinophils measured by flowcytometry.</p><p><b>RESULTS</b>Purified eosinophils did not express CD69. But eosinophils cultured with PMA + MA, IFN-gamma, IL-5 or GM-CSF expressed CD69 strongly. Eosinophils from blood of WO, WS group did not express CD69 at all. The numbers of eosinophils in BALF of WO group, IOE group, ISE group and IOE + antiCD4mAb group were significantly higher than in mice of WS group which did not have eosinophils at all. CD69 expression on eosinophils in BALF of IOE and WO groups was strong. Eosinophils in BALF of ISE and IOE + antiCDmAb groups did not express CD69. The mucus production result was similar to CD69 expression. There were eosinophils infiltration in lung slides of all groups except WS group.</p><p><b>CONCLUSION</b>Activation in airway of eosinophils could directly lead to airway inflammation.</p>

The expression of transforming growth factor beta-1 in rat model of chronic obstructive pulmonary disease and the effects of early drugs intervention / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To evaluate the expression of transforming growth factor beta-1(TGF-beta1) and the effects of early drugs intervention of chronic obstructive pulmonary disease(COPD) in rat model.</p><p><b>METHODS</b>The COPD rat model (group B) was established by intratracheal instillation of lipopolysaccharide twice and daily exposure to cigarette smoking. Drug intervention groups received dongchongxiacao orally daily from the three days before the experiment (group C) and erythromycin by intraperitoneal injection since the third week (group D)and inhalation of budesonide since the forth week (group E). At the end of 10 weeks, all 40 rats including normal control (group A) were assessed for lung resistance (RL) and dynamic lung compliance (Cdyn). The expression of TGF-beta1 gene and protein were also observed by immunohistochemistry and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively.</p><p><b>RESULTS</b>The changes of pathology and pathophysiology in rat COPD model were similar to those of human COPD. There was a significant increase in the smooth muscle and collagen thickness in the airway wall of the group B in comparison with that of the group A. RL in group B was significantly higher than that in group A (P<0.01), while it was inhibited by early drugs intervention (P<0.01). Cdyn was decreased in group B as compared with that in group A, which was limited by erythromycin and budesonide intervention (P<0.01). The relative content for TGF-beta1 was significantly increased in the epithelial cells of the bronchi, endothelial cells of the pulmonary small vessel and alveolar macrophages of COPD group as compared with those of normal controls (P<0.01).The relative contents for TGF-beta1 in the epithelial of bronchi in group D and group E were significantly lower than that in group B, but not found in group C. There was no difference between group D and group E. There were statistical positive relationships between the RL and the relative content for TGF-beta1 in the bronchial epithelial cells, between the RL and the mRNA level of TGF-beta1 in the lung tissue (P<0.01 approximately 0.05).</p><p><b>CONCLUSION</b>This rat COPD model could be helpful to obtain more information about airway remodeling. TGF-beta1 may play an important role during the process of airway remodeling, and could be influenced by early drugs intervention such as budesonide and erythromycin, which may imply their potency in the treatment of COPD. But there is not same phenomenon found in dongchongxiacao group.</p>