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Major advances in respiratory medicine in China

LIU, Hong-ju; SHI, Huan-zhong

doi: 10.3760/cma.j.issn.0366-6999.2009.17.017
Medical progress
Free
SDC

Department of Respiratory Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China (Liu HJ and Shi HZ)

Correspondence to: Dr. SHI Huan-zhong, Department of Respiratory Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China (Email: shihuanzhong@sina.com)

The authors do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received March 27, 2009)

Edited by WANG Mou-yue

Respiratory disease is the term for diseases of the respiratory system. These diseases range from mild and self-limiting such as the common cold to life-threatening such as bacterial pneumonia or pulmonary embolism. They are common and important causes of illness and death. In the US, people suffer 1 billion colds per year. One out of 7 people in the UK are affected by some kinds of chronic lung diseases, most commonly chronic obstructive pulmonary disease (COPD) and asthma. Respiratory disease accounts for over 10% of hospitalizations and over 16% of deaths in Canada.

In China, respiratory diseases are the third leading cause of death, accounting for 1 million deaths and over 5 million disabilities each year. With the economy extraordinarily expanding, researchers have been working more and more in respiratory diseases, and they have made remarkable advances in the basic and clinical medical research of respiratory medicine. Here we review the data reported by Chinese researchers in the last few years, and try to mainly focus on the respiratory diseases' progress, their mechanisms, developing factor and novel treatment of COPD, asthma, lung cancer, severe acute respiratory syndrome (SARS), adult respiratory distress syndrome, pulmonary infections, pulmonary embolism and obstructive sleep apnea syndrome (OSAS).

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CHRONIC OBSTRUCTIVE PULMONARY DISEASE

COPD ranks first among the burdens of diseases in China and is predicted to rank as the fifth burden of diseases in the world by 2020 according to an estimate by the World Health Organization.

A large-population, spirometry-based, cross-sectional survey found that the prevalence of COPD was significantly higher in rural residents, elderly patients, smokers, in those with lower body mass index, less education, and poor ventilation in the kitchen, in those who were exposed to occupational dusts or biomass fuels, and in those with pulmonary problems in childhood and family history of pulmonary diseases.1 It was also found that indoor pollutants from biomass fuels may be an important risk factor for COPD in rural South China. The importance of partly genetic susceptibility in COPD has been revealed. The polymorphisms of EPHX1 113 and EPHX1 139 are genetic contributors to COPD susceptibility in Asian populations. The phenotypes of EPHX1 were contributors to overall COPD susceptibility.3 Tumor necrosis factor (TNF)-alpha and ErbB3 are also involved in the pathogenesis of COPD. Transcatheter arterial chemoembolization (TACE) contributes to the progress of COPD indirectly through the function of TNF-alpha and ErbB3.

A randomized, double-blind, parallel-group, placebo-controlled study demonstrated that non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Mucolytics, such as carbocisteine, was well tolerated in Chinese patients with COPD.5 And another showed that low-dose, slow-release oral theophylline is effective and well-tolerated in the long term treatment of stable COPD although it does not improve post-bronchodilator lung function.6 Salmeterol/fluticasone propionate (Seretide, GlaxoSmithKline, UK) therapy achieved sustained improvement in lung function, quality of life, and control of symptoms, and was well tolerated in Chinese patients, and greater improvements in lung function were found only for COPD patients with a history of smoking.7

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ASTHMA

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. Eosinophils are characteristically present within the airway lumina of asthmatics, and also induced in vivo to express major histocompatibility complex II complexes and costimulatory molecules for T lymphocytes to be functionally activated.8 Airway luminal eosinophils can migrate into draining paratracheal lymph nodes, localize at T cell-rich paracortical areas, and stimulate antigen-specific T cell proliferation in vivo. Furthermore, eosinophils actively modulate immune responses by amplifying Th2 cell responses in vivo.9,10 The migration and in situ differentiation of CD34+ progenitors contribute to inflammatory eosinophilia; treatment with anti-chemokine receptor 3 can inhibit the migration and differentiation of CD34+ progenitor cells in asthmatic mice.11 Asthmatic rats expressed high levels of interleukin (IL)-4 and expressed more Th2 cytokines after antigen challenge.12 Airway epithelial cells may play as both inflammatory initiators and immuno-pathological feedback regulation between allergic rhinitis and asthma via release of systemic inflammatory mediators.13 The clinical study from asthma patients indicated that different extents of B7-1/B7-2-CD28/CTLA-4 molecules were expressed on the surface of various cells and their concentrations of soluble form elevating in the sera of asthma patients.14,15 And this is very important in the Th1/Th2 balance.16 Suppression by CD4+CD25+ T cells is decreased in allergic individuals. The immunomodulatory properties of CD4+CD25+ T cells do extend to Th2 responses by notably limiting the development of a proinflammatory Th2 phenotype characterized by reduced cytokine production.17 Liu et al18 studied a sample of 120 asthmatic patients and 116 healthy control subjects from the Chinese Han population and examined three polymorphic sites: ADA1, ADA2, and ADA6 within the ADA gene. The results suggest the presence of some DNA sequences influencing the susceptibility to asthma that are located in the area between ADA1 and ADA2 sites. This may be a new therapeutic strategy to treat asthma.

Mycobacterium bovis Bacillus Calmette-Guérin vaccination has been shown to inhibit allergic airway inflammation in animal models, associated with the modulation of Th1/Th2 cytokine production in early-, but not in late-challenged mice.19 More researches are required to determine the precise role of the targeted therapy in the allergic airway inflammation that will help to establish the position of potent combinations of such therapeutic regimens for the treatment of asthma.20 A investigation performed by a questionnaire in a face-to-face method in 527 asthmatic outpatients showed that the asthma control level improved further and the knowledge for disease management also improved obviously with the implementation of patient education program and asthma guideline.

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SEVERE ACUTE RESPIRATORY SYNDROME

SARS is a newly described respiratory infection with pandemic potential. The causative agent is a new strain of coronavirus most likely originating from wild animals. Factors associated with the ward environment and administration were important in nosocomial outbreaks of SARS.22 What we have experienced during SARS outbreaks has great implications for the protection of people against a resurgence of SARS and potential attacks of high-pathogenic avian flu viruses.23,24

The pathogenesis of SARS appears to be multifactorial and complex. The most plausible and possible mechanism appears to consist of a direct injury to the target cells by the SARS-CoV and an indirect injury mediated by subsequent immune system dysfunction.25 The prompt elevation of IL-6, IL-8, and monocyte chemoattractant protein-1 is a sign of superinfection, indicating a high risk of death.26 SARS coronavirus is capable of infecting the central nervous system and monokine might be involved in the brain immunopathology of SARS.27 Detection of SARS coronavirus N199 protein by ELISA is feasible in both clinical diagnosis and SARS coronavirus reservoir screening.28 Kang et al29 also developed a mass spectrometric decision tree classification algorithm which was suitable for preliminary assessment of SARS and could potentially serve as a useful tool for early diagnosis.

SARS patients may be protected from recurrent SARS coronavirus infection for up to 2 years.30 The animal study illustrates the prospects for short interfering RNA to enable a massive reduction in development time for new targeted therapeutic agents.31 A retrospective study revealed that SARS cases did not benefit from corticosteroid on the death rate and hospitalization days but getting lower overall mortality, instant mortality and shorter hospitalization stay.

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PLEURAL DISEASES

Aquaporin-1 may be involved in fluid transport in numerous pathological conditions. The expression of aquaporin-1 was present in rat pleural mesothelial cells. Aquaporin-1 was found to be increased in tuberculous pleural effusion (TPE) and may be involved in the formation of TPE.33 The application of short hairpin RNA-aquaporin-1 could markedly inhibit the expression of aquaporin-1 in cultured rat pleural mesothelial cells. The use of RNA interference is a promising tool for future research into the mechanisms of pleural fluid in vivo.34

Lymphocytic pleural effusions refer to those in which lymphocytes account for more than 50% of total leukocytes in pleural effusion. Lymphocytic effusions are relatively common (> 90% of cases) result of malignancy and tuberculosis pleurisy.35 CD4+CD25+ regulatory T cell numbers were increased in malignant pleural effusion (MPE) and in TPE.36 It could potently suppress the proliferation of CD4+CD25- T cells and cytotoxic lymphocyte-associated antigen-4 was involved in its suppressive activity.37 CD4+CD25+ T cells might also be recruited into pleural space by local production of IL-16 or by chemokine CCL22 produced by pleural cells.38

Making a differential diagnosis between TPE and MPE is a critical clinical problem. Many studies have suggested IFN-γ determination is a sensitive and specific test for the diagnosis of tuberculous pleurisy.39,40 Its overall accuracy seemed to be somehow better than that of adenosine deaminase although adenosine deaminase assays also play a potential role in confirming a diagnosis of TPE.40

To improve the diagnosis of MPE, carcinoembryonic antigen (CEA) is the most common marker to have been studied extensively and has been found to be a useful diagnostic tool for confirming MPE, and is also helpful in the differential diagnosis between malignant pleural mesothelioma and metastatic lung cancer.41 The current evidence does not recommend using one of CA 125, CA 15-3, CA 19-9 and CYFRA 21-1 alone for the diagnosis of MPE, but the combination of two or more tumour markers seems to be more sensitive based on a meta-analysis.42 In addition, determination of pleural soluble triggering receptor expressed on myeloid cells-1 may improve the ability of clinicians to differentiate pleural effusion patients with bacterial pleural infection from those with the other etiologies.

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PULMONARY INFECTIONS

The pathogenesis of Pseudomonas aeruginosa pneumonia in immunosuppressed patients is not understood completely. Xu et al44 have demonstrated keratinocyte growth factor expressions of pneumonia in immunosuppressed rats were less than those in immunocompetent ones.

It is worthy of mention, invasive pulmonary aspergillosis is a common and devastating pneumonia. Recent results showed that dendritic cells engulfed Aspergillus conidia through coiling phagocytosis. IL-12-engineered dendritic cells augmented their protection from aspergillosis pneumonia strikingly as judged by a higher survival and a pronounced enhancement in the aspergillus-specific IFN-γ response.45 These show that antigen-pulsed dendritic cells and IL-12 gene therapy could be used as an adjunct therapy for aspergillosis.

Zhan et al46 described the clinical features of invasive pulmonary aspergillosis (IPA) in critically ill patients with chronic respiratory diseases (CRD) and estimated their value for early diagnosis and treatment. With the rapid progression of infiltrates, bronchial pseudomembrane was observed, with increased white blood cell count and exacerbated radiologic findings. All patients with early antifungal treatment before the appearance of infiltrates survived. So IPA occurring in critically ill CRD patients is not rare and has a poor prognosis. Early diagnosis and empirical antifungal treatment based on certain clinical features may improve the outcome.

As for avian influenza, recently, He et al47 have demonstrated the details of structure of avian AIV virus for the binding of PB1 (N) to PA (C) at the atomic level. A phase I randomised controlled trial done in 120 Chinese volunteers48 suggested that a lower doses of inactivated whole-AIV vaccine with aluminium hydroxide adjuvant could achieve immune responses equivalent to those elicited by adjuvanted or non-adjuvanted split-virion vaccines. Actually, the results from a clinical case also indicate that passive immunotherapy should be a viable option for the treatment of AIV infection.49

Recently, there is great progress of mucus hypersecretion.50 Mucus hypersecretion is a distinguishing feature of chronic inflammation diseases, such as asthma, chronic bronchitis, bronchiectasis and cystic fibrosis. Mucus hypersecretion leads to impairment of mucociliary clearance, abnormal bacterial plantation, mucus plug in the airway, and dysfunction of gas exchange. It is accompanied by goblet cell hyperplasia and MUC gene abnormalities. Gob-5 and AQP5, a highly permeable water channel, might be important genes in regulating mucus hypersecretion of asthma. Airway epithelial cells have emerged as critical regulators of inflammatory networks in the chronic airway inflammation. IL-13, IL-4 and IL-9 are all important cytokines in induction of mucus hypersecretion of airway inflammation. TNF-α could lead to mucus hypersecretion by protein kinase C (PKC) signal transduction. Furthermore, much attention has been paid to the important role of epithelial growth factor receptor (EGFR) involving in the hyperproduction of mucus and epithelial proliferation. Myristoylated alanine-rich C kinase substrate (MARCKS) is a central regulatory molecule. Overall, the mechanism of mucus secretion and the regulation of expression of mucins is gradually clarified.

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LUNG CANCER

The debate resolved somewhat whether cisplatin-based and carboplatin-based chemotherapy are equally effective for advanced non-small cell lung cancer (NSCLC). A meta-analysis revealed that there was not a survival advantage in the cisplatin or carboplatin group.51 A recent meta-analysis52 shows that pleural lavage cytology is a strong prognostic factor for survival in patients with lung cancer. Chen et al53 studied 97 clinical NSCLC patients and found that tissue factor (TF) promoted angiogenesis, and urokinase-type plasminogen activator receptor (uPAR) contributed to lymph node metastasis and vascular involvement. Co-expression of TF and uPAR may play an important role in the metastasis and prognosis of NSCLC. As for some rare tumors, diagnosis of primary pulmonary synovial sarcoma depends on identifying epithelioid or spindle cells microscopically and on immuno-histochemistry showing positivity for cytokeratin and vimentin and epithelial membrane antigen stains.

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ACUTE LUNG INJURY/ACUTE RESPIRATORY DISTRESS SYNDROME (ALI/ARDS)

The treatment for ARDS was still paid close attention to recently, and curcumin (CUR) has been reported to be an alternative therapy for protecting lung transplantation-associated ALI by suppressing nuclear factor-κB-mediated expression of inflammatory genes.55

Bone marrow-derived mesenchymal stem cells and angiopoietin-1 have a synergistic role in the treatment of lipopolysaccharide (LPS)-induced acute lung injury (LPS-ALI). Bone marrow-derived mesenchymal stem cells-based angiopoietin-1 gene therapy may be developed as a potential novel strategy for the treatment of ALI.56

Sun et al57 observed curcumin attenuated acute lung injury probably through improving oxidative stress and inhibiting nuclear factor-kappa B-mediated expression of inflammatory cytokines. Thus, curcumin may be an alternative therapy for improving the outcomes of ischaemia-reperfusion-induced lung injury. And Jin et al58 indicated the elevated serum IL-6 level in ARDS patients seemed to be correlated well with the severity of lung injury, and appeared to be a good marker to judge the prognosis of the disease combined with acute physiology and chronic health evaluation (APACHEII) score. In the early phase of ARDS, continuous renal replacement therapy (CRRT) can decrease the high serum level of IL-6, shorten the duration of total mechanical ventilation and ICU stay, and decrease the incidence of ventilator associated pneumonia (VAP). Thus CRRT may be one of the most vital methods to treat ARDS.

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PULMONARY EMBOLISM

The fibrinolytic function of endothelial cells plays an important role in the pathophysiology of pulmonary vascular diseases. The combination of urokinase-type plasminogen activator with urokinase-type plasminogen activator receptor may be a critical pathway for the induction of urokinase-type plasminogen activator expression.59 The exploration of various proteins or their combination with existent markers such as D-dimer may greatly improve the accuracy of the diagnosis of acute pulmonary embolism.60 Thromboendarterectomy is an effective treatment for chronic pulmonary thromboembolism.61 Right ventricular dysfunction, right and left ventricular end-diastolic diameter ratio, and cardiac troponin I are independent predictors of 14-day clinical outcomes. Early detection of right ventricular dysfunction was beneficial for identifying high-risk patients.62,63

Pang et al64 and Yin et al65 concluded by clinical study that apparent imbalance in the blood coagulative and fibrinolytic system and pulmonary vascular endothelium damage occurred in the patients with acute pulmonary thromboembolism (PTE). Combination tests of plasma D-dimer, antithrombin-III, protein S, protein C, thrombomodulin, tissue-type plasminogen activator and plasminogen activator inhibitor-1 can give a more comprehensive explanation of the imbalance in the blood coagulative and fibrolytic system. Anticoagulant treatment and thrombolytic treatment play important roles in the regulation of the imbalance of coagulative and fibrinolytic system and protection of the function of pulmonary vascular endothelium of PTE patients.

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OBSTRUCTIVE SLEEP APNEA SYNDROME

For patients with OSAS, the meta-analysis shows that continuous positive airway pressure does not improve general quality of life (QOL) scores but does improve physical domains and vitality. Study design and QOL questionnaire tools are important to capture and evaluate information efficiently. However, generic QOL instruments may not be adequate in detecting important changes in QOL in patients with OSAS.

Yue et al67 also studied serotonin transporter gene polymorphisms of Chinese patients with OSAS and found the serotonin (associated with circadian rhythm and breathing regulation) transporter gene may be involved in susceptibility to OSAS, especially with male-dependent effect.

When OSAS patients with hypertension, their movement arousal and hypoxia may make an important contribution to circardian elevation of blood pressure. Both of them may result in the development of nocturnal and diurnal hypertension in patients with OSAS.

At the meantime, OSAS may predispose patients to congestive heart failure, suggesting a deleterious effect of OSAS on myocardial contractility. Right and left myocardial performance index (MPI) correlated positively and significantly with apnea-hypopnea index (AHI). So OSAS is associated with impaired right and left ventricular function.

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CONCLUSIONS

Compared with the work performed decades ago, lots of exciting achievements have been made in respiratory medicine during the past 5 years. The molecular mechanism of respiratory diseases has been better understood. Efficient prevention and therapy method reduces morbidity and mortality of respiratory diseases. Especially, many studies have involved molecular immune, targeted and gene therapy. Though the field is still in its infancy, their movement into clinical trails of some therapies is deeply encouraging. The clarification of the mechaniam, developing factor and therapeutic targets in the respiratory diseases have provided us with a vital opportunity to reassess the danger, a spacious window to foresee the prognosis, and the great opportunity to develop new therapeutic strategies for respiratory diseases.

However, it should be mentioned that we do not have much cutting edge findings in the studies of respiratory diseases. We are lacking in evidence-based medical researches concerning the diagnosis of therapy in the clinical practice. Moreover, because of the inaccessibility of human lung and the difficulties in obtaining histological samples in humans, part of our medical progress of respiratory diseases comes from experimental studies. So it is important to notice the differences between humans and animals in studies, to notice working with enough novelty and merits modern experimental tools, such as transgenic or knock-out mice in the basic. We also need to emphasize on organizing more and more multicenter, randomized, double-blind, parallel-group, placebo-controlled trials in the clinical studies.

To sum up, the ultimate goal for study of respiratory diseases is to circumvent the diseases' processes that result in mental or physical decrease and thus to prevent from diseases formation in air tube or lungs. More clinical work and further studies should be done on the respiratory diseases.

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      Keywords:

      chronic obstructive pulmonary disease; asthma; severe acute respiratory syndrome; pleural diseases; pulmonary infections; lung cancer; acute lung injury/acute respiratory distress syndrome; pulmonary embolism; obstructive sleep apnea syndrome

      © 2009 Chinese Medical Association