Pathogenesis of Idiopathic Pulmonary Fibrosis and Modulating Effect of Chinese Medicine： A Review / 中国实验方剂学杂志

Idiopathic pulmonary fibrosis （IPF）， as a progressive lung disease， has a poor prognosis and no reliable and effective therapies. IPF is mainly treated by organ transplantation and administration of chemical drugs， which are ineffective and induce side effects， failing to meet the clinical needs. Therefore， developing safer and more effective drugs has become an urgent task， which necessitates clear understanding of the pathogenesis of IPF. The available studies about the pathogenesis of IPF mainly focus on macrophage polarization， epithelial-mesenchymal transition （EMT）， oxidative stress， and autophagy， while few studies systematically explain the principles and links of the pathogeneses. According to the traditional Chinese medicine theory， Qi deficiency and blood stasis and Qi-Yang deficiency are the key pathogeneses of IPF. Therefore， the Chinese medicines or compound prescriptions with the effects of replenishing Qi and activating blood， warming Yang and tonifying Qi， and eliminating stasis and resolving phlegm are often used to treat IPF. Modern pharmacological studies have shown that such medicines play a positive role in inhibiting macrophage polarization， restoring redox balance， inhibiting EMT， and regulating cell autophagy. However， few studies report how Chinese medicines regulate the pathways in the treatment of IPF. By reviewing the latest articles in this field， we elaborate on the pathogenesis of IPF and provide a comprehensive overview of the mechanism of the active ingredients or compound prescriptions of Chinese medicines in regulating IPF. Combining the pathogenesis of IPF with the modulating effects of Chinese medicines， we focus on exploring systemic treatment options for IPF， with a view to providing new ideas for the in-depth study of IPF and the research and development of related drugs.

The possibility of phosphodiesterase 4 inhibitors as drug therapy for idiopathic pulmonary fibrosis / 中国临床药理学与治疗学

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and typical chronic fibrotic lung disease. In recent years, significant progress has been made in the pathophysiology, clinical diagnosis and treatment of IPF. However, to date, there is still no cure for IPF. The second messenger cyclic adenosine monophosphate (cAMP) inhibits fibroblast proliferation or differentiation into myofibroblasts during the development of IPF. Phosphodiesterase 4 (PDE4) is a major camp-degrading enzyme in lung fibroblasts, which is up-regulated during the progression of fibrosis. PDE4 inhibitors have anti-fibrosis effects in vivo and in vitro in IPF models. In addition, PDE4 is widely involved in inflammatory processes, which are also active in the pathogenesis of IPF. Thus, PDE4 inhibition is a potential therapeutic approach for IPF. This article reviews the pathogenesis of IPF and the physiological function of PDE subtype 4 inhibitors in the treatment of IPF.

Metabonomic Analysis of Wenfei Huaxian Granules Against Idiopathic Pulmonary Fibrosis in Mice / 中国实验方剂学杂志

ObjectiveTo investigate the changes of differential metabolites in the serum of mice at different stages of bleomycin sulfate（BLM）-induced pulmonary fibrosis modeling and administration， and the mechanism of Wenfei Huaxian granules（WHG）against idiopathic pulmonary fibrosis. MethodMice were randomly divided into control group， control group of 14 days， model group， model group of 14 days， low-dose WHG group and high-dose WHG group. BLM（0.04 U per mouse）was injected into the trachea of mice in the model group， model group of 14 days， low-dose WHG group and high-dose WHG group， and sterile normal saline was injected into the trachea of mice in the control group and control group of 14 days. Mice of low-dose WHG group and high-dose WHG group were given different doses of WHG by gavage every day after injection of BLM， and mice of control group， control group of 14 days， model group and model group of 14 days were given sterile water by gavage every day. The peripheral blood of mice in the control group of 14 days and model group of 14 days were taken to prepare serum after injection of BLM for 14 days， and the peripheral blood and other materials of mice in the other groups were taken after continuous administration for 28 days. The bronchoalveolar lavage fluid（BALF）was collected for leucocyte differential count， the pathological examination and hydroxyproline（HYP）content determination of lung tissues of mice were performed， and the small molecule metabolites in serum samples of mice in each group were determined by ultra-high performance liquid chromatography-mass spectrometry（UHPLC-MS）. Principal component analysis（PCA）and orthogonal partial least squares-discriminant analysis（OPLS-DA）were conducted to screen differential metabolites and their biological functions were analyzed. ResultCompared with the control group， a large number of continuous fibrotic foci appeared in the lung tissue of mice in the model group， the alveolitis score， fibrosis degree score and HYP content increased significantly（P<0.01）， and the total number of leukocytes， macrophages and lymphocytes in BALF increased significantly（P<0.05）. A total of 33 differential metabolites were screened between the control group of 14 days and model group of 14 days， mainly lipid metabolites， which were mainly involved in oxidative damage and inflammatory process. A total of 34 differential metabolites， mainly amino acid metabolites， were screened between the control group and model group， mainly involving nucleic acid damage and inflammatory process. Compared with the model group， the HYP content， fibrosis score and alveolitis score in the lung tissue of mice from high-dose WHG group decreased significantly（P<0.05， P<0.01）， and the total number of lymphocytes in BALF decreased significantly（P<0.05）. Compared with the model group， 27， 40 differential metabolites were identified in the serum of mice from the low-dose WHG group and high-dose WHG group separately. There were totally 9 common differential metabolites between the model group and low-dose WHG group/high-dose WHG group， which mainly involved in the metabolic pathways of inflammation related lipids metabolism， arginine and tryptophan metabolism， and the change trends in low-dose WHG group and high-dose WHG group were significantly back-regulated compared with the model group. ConclusionWHG can alleviate BLM-induced pulmonary fibrosis， collagen deposition and inflammatory reaction in mice， and its anti-fibrotic effect may be related to the adjusting of inflammatory factors， nitric oxide and oxidative stress related metabolic pathways.

A brief review on Pleiotropic effects of Pirfenidone - novel and ongoing outcomes

Presently, there is a huge hype and excitement in the field of synthetic biologics and engineering regarding growing cases of their implication in various fields including health care systems. Furthermore, despite its large body of suggestive and fascinating accomplishments, the synthetic area is always been subject of much more prejudice and debate. However, over a couple of years, the generation of researchers had tested one of such disease modifying compound Pirfenidone (Esbriet®), to unleash their potential in the different disciplines of interventional pharmacology and therapy. In this pipeline, depending on its success of multiple missions, in context to advancing the therapy for different diseases, it became the first prescribed medicine to treat the people with one characteristic lung disorder called idiopathic pulmonary fibrosis (IPF). This review discusses the different therapeutic strategies beyond its well-known anti-fibrotic activity in several well-characterized animals, cell-based and human models and also regarding facts of Pirfenidone (PFD) as anti-inflammatory, anti-fibrinogenic, anti-oxidants including in the treatment of diabetic neuropathy, liver cirrhosis etc. This review also contains current investigations, focusing mainly on the novel findings and their outcomes in improving the quality of life of patients with different conditions and also suggests their implication on the basis of fundamental existential evidences to break the major impediment in transforming this disease-modifying drug into a personalized medicine.

Immature platelet fraction in children infected with dengue fever

Background: Millions are infected with dengue every year.' Early diagnosis of dengue infection is important for proper treatment of DHF and DSS to avoid fatal outcome. Thrombocytopenia is a common hematological abnormality in dengue, which demands platelet transfusion in most of the severe dengue cases. Platelet transfusion though life-saving has its own hazards. Hence, we can use some new parameter like immature platelet fraction (IPF) which is a measure of reticulated platelets that reflects the rate of thrombopoiesis. The risk of platelet transfusion may be decreased by rapid identification of immature platelet fraction. This study was performed to establish reference of IPF values for the assessment of thrombopoiesis.Methods: Blood samples from 150 children were obtained on day of illness 3, 5 and 7. The IPF is identified by sysmex XE2100 hematology analyser in the reticulocyte channel using a fluorescent dye and a carefully designed gating system and counted by a special software termed IPF master7. IPF values against platelet count were assessed separately on day 3, 5 and 7.Results: The reference intervals of IPF > 8 % and IPF < 8 % were assessed against platelet count. Increase in IPF favored increase in platelet count on day 5 which was statistically significant with the p value <0.001.Conclusions: A rapid and inexpensive automated measurement of IPF can be integrated as a standard parameter to evaluate the thrombopoietic state of the bone marrow. From the study it can be concluded that IPF is an important predictor of increase in platelet count.' Increase in IPF>8 % suggests that platelet count will be increased in next 24 to 48hrs indicating that further blood transfusion will not be required.

Dendrometric evaluation of a clonal population of Tectona grandis in forest-livestock system / Levantamento dendrométrico de um povoamento clonal de Tectona grandis, em sistema silvipastoril

ABSTRACT: Production of Tectona grandis (teak) in integrated systems with livestock or agriculture demonstrates high potential of financial return. However, studies on the development of teak are still scarce, especially in the northern region state of Mato Grosso. In this study we sought to evaluate dendometric variables of a clonal population of teak in a forest-livestock integration system (LFIS), during a period of 53 months in the city of Alta Floresta, Mato Grosso, Brazil. For this purpose, three installments were samples, a total of 360 individuals, and for each the diameter was measured at 1.3 meters from the base so as to calculate the total volume, the current annual increment (CAI) and mean annual increment (MAI), and five adjusted regression models. The Hoerl model provided the highest adjusted coefficient of determination (R2aj), lowest standard error of estimate (Syx), coefficient of variation (CV %), and from this the growth curves were developed. Clonal stands of teakin the forest-livestock system presented increases in DBH, height and volume were superior in relation to other scientific studies with teak, indicating their viability in integrated systems with pastures in the region.

RESUMO: A produção de madeira de Tectona grandis (teca) em sistemas integrados com pecuária ou agricultura demonstra alta perspectiva de retorno financeiro. Entretanto, estudos sobre o desenvolvimento da teca ainda são escassos, principalmente na região norte de Mato Grosso. O objetivo do trabalho foi avaliar o crescimento das variáveis dendrométricos de um povoamento clonal de teca, em um sistema silvipastoril (iPF), ao longo de 53 meses, no município de Alta Floresta-MT, Brasil. Para isso, foram amostradas três parcelas, totalizando 360 indivíduos, sendo que em cada indivíduo foi mensurado o diâmetro a 1,3 m do solo e altura total. Em seguida realizou-se o cálculo do volume. Para descrever o crescimento da variável diâmetro, altura total e volume foi realizado o ajuste através de cinco modelos matemáticos que expressam o crescimento ao longo do tempo. Posteriormente, foram calculados o incremento corrente anual (ICA) e incremento médio anual (IMA). O modelo de Hoerl apresentou melhores resultados de R²aj, obteve menores valores para o erro padrão de estimativa (Syx) e para o CV%, com isso, foi selecionado para a elaboração das curvas de crescimento. O povoamento clonal de teca no iPF apresentou incremento em DAP, Altura e volume foram superiores em relação a outros estudos científicos com teca, indicando sua viabilidade em sistemas integrados com pastagens na região.

Experience with the Compassionate Use Program of nintedanib for the treatment of Idiopathic Pulmonary Fibrosis in Argentina

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a diffuse lung disease (DLD) of unknown etiology that is chronic and progressive. It occurs in older adults; it is restricted to the lungs and it is associated with the anatomopathological and/or tomographic pattern of Usual Interstitial Pneumonia (UIP). The evolution of the disease is progressive and it is associated with a mean 5-year survival rate of 20%. Objectives: to identify the clinical and pulmonary function characteristics in the group of patients with IPF included in the Compassionate Use Program (NPU, Named Patient Use); to identify the safety profile reported with nintedanib. Materials and methods: a retrospective, descriptive and cross-sectional study including 54 patients enrolled in the NPU program from September 1st, 2015 to August 10th, 2016. Data were collected from the NPU program records. Results: fifty-four patients with IPF were included in the NPU program, of whom 47 received nintedanib; the data from the latter were analyzed. Thirty-seven (78.72%) were males, with a mean age at the beginning of treatment of 67.47 ± 7.85 years, and in 9 cases (19.14%) the diagnosis was confirmed by lung biopsy. The mean forced vital capacity (FVC) at the beginning of treatment was 65.87±19.23 and it is presented as the percentage of the predictive value; the mean carbon dioxide diffusing capacity (DLCO) presented as the percentage of the predictive value was 38.74 ± 3.09. The time of progression from the diagnosis of IPF to the beginning of the treatment with nintedanib was 27.17± 27.9 months (median 17). Average drug exposure to cut-off point was 9.92 weeks ± 2.15 (median: 10 weeks). In 7 cases (31.91%) the FVC was over 80%, in 22 (46.80%) cases it was between 50 and 79% and in 10 cases (21.27%) it was below 49%. In total, 7 patients (14.89%) exhibited adverse events: Five (10.6%) patients exhibited weight loss, 4 (8.51%) diarrhea, 2 patients had nausea, 1 (2.12%) an increase of the liver enzymes and 1 (2.12%) pruritus. In most cases, the adverse events appeared during the first 2 weeks after beginning the treatment with nintedanib. In 3 (6.38%) cases it was imperative to suspend nintedanib permanently due to the adverse effects and in 4 (8.51%) cases the dose had to be titrated to 100 mg every 12 hours. Out of the total of patients, 6 (12.76%) passed away due to the progression of their underlying disease. Conclusions: such as it was reported by other groups, nintedanib has a manageable and tolerable safety profile. In our series of 47 patients with IPF who received at least one dose of nintedanib, 14.89% had an adverse event that led to the permanent discontinuation of the drug in only 3 patients (6.38%).

Antifibrotic effect of TY501 on bleomycin-induced pulmonary fibrosis in rats and related mechanism / 中国药理学通报

Aim To investigate TY501′s role in bleo-mycin ( BLM )-induced pulmonary fibrosis in rats. Methods Forty rats were randomly divided into 5 groups, including the sham operation, BLM, PFD, TY501(high and low dose) groups. After administra-tion of BLM intratracheally, PFD and TY501 were giv-en in each group daily, according to the dosage de-signed during 21 days. Lung coefficient, PaO2 were tested before killing the rats. The contents of ALB, ALP, LDH, GSH, HYP were detected by regent kit respectively. PCⅢ and COL4 were determined by ELISA. Results ( 1 ) Some indicators of alveolitis in early stage of IPF: the contents of lung coefficient in three treatment groups were lower and PaO2 was higher than those in BLM group ( P<0. 05 ); compared with BLM group, the contents of ALB, ALP, LDH in the treatment groups reduced on 21 st day ( P<0. 05 );the expression of GSH in BLM group was increased for feedback regulation and higher than the treatment groups and the sham operation group (P<0. 05);(2) some indicators of pulmonary interstitial fibrosis in late stage of IPF:the expressions of HYP, PCⅢand COL4 were reduced after the treatment. There were signifi-cant differences compared with BLM group ( P <0. 05 ) . Conclusions TY501 is valuable for the ther-apy of IPF, the same as the positive drug pirfenidone. TY501 attenuates BLM-induced pulmonary fibrosis, which may be related to the affection of TGF-βpathway and inhibition of MMPs.

On Life Quality Evaluation of IPF Patients / 中华中医药杂志

Objective: To Study the effects and feasibility of life quality list for idiopathic pulmonary fibrosis(IPF) patients.Methods: Applying the self-made life quality evaluating list,life qualities of 36 cases of IPF patients were analyzed and compared before and after the intervention of traditional Chinese medicine.Results: The evaluating list of life quality is available for IPF patients.Conclusion: The evaluation of life quality is an available method for the observations of clinical therapeutic effect and health status on IPF patients and it is worth further investigation.

The effect of Feixian Fang treating the idiopathic pulmonary fibrosis patients in MMPs and TIMPs / 中华中医药杂志

Objective:To research the therapeutic effect dnd pulmonary ground substance rebuilding in the treatment on IPF patients by Feixian-Fang and.Methods:Treatment 20 cases IPF by Feixian Fang RCT prednisone three months.obsive The therapeutic efficacy and the levels of matrix met alloproteinase 1,2,tissue inhibtor of met alloproteinase(TIMP-1,2).Results: The total effective rate of Feixian-Fang group is 84.2%.The total effective rate of prednisone group is 81.3%.Feixian-Fang can reduce the level of MMP-1,MMP-2,TIMP-1,TIMP-2 in the serum.Concluds:Feixian-Fang can treat IPF probably through inhibiting pulmonary ground substance rebuilding.

Clinical Course of Probable Idiopathic Pulmonary Fibrosis / 결핵및호흡기질환

BACKGROUND: According to the 2002 consensus report of the American Thoracic Society/European Respiratory Society (ATS/ERS), idiopathic pulmonary fibrosis (IPF) was classified as biopsy proven or probable IPF. Probable IPF is defined as those with distinctive features that allow for a confident diagnosis of IPF/usual interstitial pneumonia (UIP) within an appropriate clinical setting. The determination of the clinical course of probable IPF, as diagnosed by the ATS/ERS criteria, was studied. METHODS: Between March 1995 and August 2002, 36 patients with probable IPF, from two tertiary referral hospitals, were enrolled in this study. The clinical characteristics, prognostic factors and treatment efficacy of these patients were retrospectively evaluated. RESULTS: The mean age of the subjects was 65 +/- 6 years. The one and 3 year survival rates were 82.4 and 50.3%, respectively, and a median survival period of 42.0 months. The total cell count of bronchoalveolar lavage was higher in the death than the survival group (p<0.05). No survival benefits were found in the cytoxan and steroid treatment groups compared with other treatment groups. CONCLUSION: These results suggest that the clinical course of probable IPF may be similar to that of biopsy-proven UIP. However, atypical patients must undergo an open lung biopsy for confirmation of the diagnosis.

A Case of Nonspecific Interstitial Pneumonia with Clinical Course of Rapid Aggravation / 결핵

Nonspecific interstitial pneumonia (NSIP) was first described as a new category of idiopathic interstitial pneumonia in 1994. This is a disease with a more insidious onset and has a chronic course. The histological findings are unusual for other idiopathic interstitial pneumonia cases (usual interstitial pneumonia, diffuse interstitial pneumonia, and acute interstitial pneumonia). In contrast to NSIP, acute interstitial pneumonia (AIP) has an acute onset and a fulminant course with the rapid development of respiratory failure. A pathological examination demonstrated characteristic diffuse interstitial fibrosis, hyaline membranes, thrombi, and architectural derangement. Here we report a 48-year-old woman who was diagnosed pathologically NSIP, but with a rapid progressive course similar to AIP.

The early diagnostic value of cardiopulmonary exercise test in IPF / 中国实用内科杂志

Objective To detect early diagnosis significance of cardiopulmonary exercise test in idiopathic pulmonary fibrosis(IPF).Methods 32 cases of IPF were individed into 2 groups,early-stage group (19cases) and non-early-stage group (13cases).All IPF patients and 22 healthy persons as control were performed cardiopulmonary exercise test.Results All indexes of cardiopulmonary exercise test were significantly different between the early-stage group and the control group,the non-early-stage group and the control group,the non-early-stage group and the early-stage group.Conclusion Cardiopulmonary exercise test markedly raises value early diagnosis in IPF.

Clinical differential diagnosis of usual interstitial pneumonia from nonspecific interstitial pneumonia / 결핵

BACKGROUND: Nonspecific interstitial pneumonitis (NSIP) is most likely to be confused with usual interstitial pneumonitis (UIP). Unlike patients with UIP, the majority of patients with NSIP have a good prognosis, with most patients improving after treatment with corticosteroids. Therefore it is clinically important to differentiate NSIP from UIP. UP to now, the only means of differentiating these two diseases was by means of surgical lung biopsy. American Thoracic Society (ATS) proposed a clinical diagnostic criterial for UIP to provide assistance to clinicians in its diagnosis without surgical lung biopsy. This study is aimed to investigate whether there were clinical and radiological differences between NSIP and UIP, and the usefulness of ATS clinical diagnostic criteria for UIP in Korea. METHODS: we studied 60 patients with UIP and NSIP confirmed by surgical lung biopsy. Clinical manifestations, pulmonary function test, arterial blood gas analysis, bronchoalveolar lavage (BAL), and high resolution computed tomography (HRCT) were evaluated and analyzed by Chi-square test or t-test. The clinical criteria for UIP proposed by ATS were applied to all patients with idiopathic interstitial pneumonia. RESULTS: Forty-two patients with UIP and 18 with NSIP were pathologically identified. Among the 18 patients with NSIP (M : F = 1 : 17), the mean age was 55.2± 8.4 (44~73)yr. Among the 42 patients with UIP (M : F = 33 : 9), the mean age was 59.5±7.1 (45~74) yr (p=0.0460. Fever was more frequent in NSIP (39%) (p=0.034), but clubbing was frequently observed in UIP (33%) (p=0.023). BAL lymphocytosis was more frequent (23%) (p=0.0001) and CD4/CD8 ratio was lower in NSIP (p=0.045). On HRCT, UIP frequently showed honeycomb appearance (36 of 42 patients) through not in NSIP (p=0.0001). Six of 42 UIP patients (14.3%) met the ATS clinical criteria for IPF, and 3 of 16 NSIP patients (18.8%) met the diagnostic criteria. CONCLUSION: Being a relatively young female and having short duration of illness, fever, BAL lymphocytosis, low CD4/CD8 ratio with the absence of clubbing and honeycomb appearance in HRCT increase the likelihood of the illness being NSIP. The usefulness of ATS clinical diagnostic criteria for UIP may be low in Korea.

Proliferative Properties and Cytokine Secretion of Lung Fibroblast Cell Lines of the Patients with Idiopathic Pulmonary Fibrosis / 결핵

BACKGROUND: It is well known that various cytokines and growth factors secreted mainly from alveolar macrophages do the key role in the pathogenesis of IPF. But recently it has been known that structural cells like fibroblast can also release cytokines. So the phenotypic changes in fibroblasts of IPF may do a role in continuous progression of fibrosis. The aim of this study is to find out whether there is a change in the biologic properties of the lung fibroblasts of IPF. SUBJECTS AND METHOD: The study was done on 13 patients with IPF diagnosed by open or thoracoscopic lung biopsy and 7 control patients who underwent resectional surgery for lung cancer. Lung fibroblast cell lines (FB) were established by explant culture technique from the biopsy or resected specimen RESULT: Basal proliferation of the fibroblast of IPF(IFB) measured by BrdU uptake tended to be highter than control fibroblast(NFB) (0.212+/- 0.107 vs 0.319+/-0.143, p= 0.0922), also there was no signifrcant difference in proliferation after the stimulation with PDGF or 10% serum. On the contrary, the degree of inhibition in proliferation by PGE2 was significantly lower(33.0+/-13.1%) in IFB than control(46.7+/-10.0%, p= 0.0429). The IFB secreted significantly higher amount of MCP-1(1574+/-1283 pg/ml) spontaneously than NFB(243+/-100 pg/ml) and also after the stimulation with TGF-beta (3.23+/-1.31 ng/ml vs 0.552+/-0.236 ng/ml, p= 0.0012). Similarly IL-8 and IL-6 seretion of IFB was significantly higher than NFB at basal state and with TGF-beta stimulation. But after the maximal stimulation with IL-1beta, no significant difference in cytokine secretion was found between IFB and NFB. CONCLUSION: Above data suggest that the fibroblasts of IPF were phenotypically changed and these change may do a role in the pathogenesis of IPF.