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Welcome to Chinese Journal of Clinical Pharmacology and Therapeutics,Today is Chinese

Table of Content

    Volume 27 Issue 6
    26 June 2022
    Oral lienal peptides improve ammonia-induced coughing and inflammation in mice
    MAO Shuying, JIN Wei, FU Sisi, LIU Keanqi, ZHOU Zhihao, WANG Guangji, LIANG Yan
    2022, 27(6):  601-607.  doi:10.12092/j.issn.1009-2501.2022.06.001
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    AIM: To study the effect of oral lienal polypeptide on cough and inflammation in mice, in order to expand the clinical application of immune modulator lienal polypeptide and provide a new strategy for relieving cough and inflammation.  METHODS: The cough model of mice was induced by concentrated ammonia. The cough frequency and tolerance latency of mice within 6 minutes were recorded every day. The histopathological changes of spleen and lung were evaluated by HE staining and spleen index. TNF-α, IL-1β and IL-6 levels in spleen and lung of mice was detected by ELISA. RESULTS: Oral administration of spleen polypeptide could prolong the tolerance latency of mice to concentrated ammonia to a certain extent and significantly reduce the cough frequency of mice. HE staining showed that oral spleen polypeptide could significantly reduce the alveolar surface area and improve lung expansion in mice. The results of ELISA showed that oral spleen polypeptide decreased the levels of some proinflammatory factors in spleen and lung. CONCLUSION: Lienal polypeptide can alleviate cough and emphysema like symptoms induced by ammonia, improve immune ability and inflammation in mice.
    Synergistic antibacterial effect of ursolic acid combined with fusidic acid on Staphylococcus aureus
    ZHANG Peng, WANG Zishu, XU Lihong, YIN Xiangnan, HU Wen, CHEN Chunlin
    2022, 27(6):  608-613.  doi:10.12092/j.issn.1009-2501.2022.06.002
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    AIM: To explore the antibacterial activity and underlying mechanism of ursolic acid combined with fusidic acid against Staphylococcus aureus (SA) ATCC29213 and Methicillin-Resistant Staphylococcus aureus (MRSA) ATCC43300 in vitro.  METHODS: The minimum inhibitory concentration (MIC) of the combined use of ursolic acid and fusidic acid on SA, MRSA was determined by the micro broth dilution method and the micro checkerboard method, and the partial inhibitory concentration index (FICI) was calculated to determine the combined effect. And the bactericidal effect of fusidic acid combined with ursolic acid was studied by the time-killing curves. The agar double dilution method was used to determine the anti-drug resistance mutation concentration (MPC) and anti-drug resistance mutation selection window (MSW) of fusidic acid alone and in combination with ursolic acid. The viable count of biofilm carrier were determined by serial dilution method and the semi-quantitative biofilm by crystal violet staining method. RESULTS: The combined use of ursolic acid and fusidic acid for SA and MRSA FICI were 0.312 5 and 0.375, respectively. The time-killing curve showed that 1MIC ursolic acid combined with 1MIC fusidic acid has a synergistic bactericidal effect on SA and MRSA. The MPC of fusidic acid to MRSA was 256 μg/mL and the MSW was 256. After fusidic acid combined with ursolic acid, the MPC decreased to 8 μg/mL. The combined group was significantly reduced compared to the fusidic acid group. The semi-quantitative and biofilm bacterial counts of combined group were markedly decreased compared to the fusidic acid group after the biofilm cultivate for 48 h and 72 h.CONCLUSION:  The combined use of UA and FA has a synergistic effect on SA and MRSA.
    Delicaflavone inhibits the invasion and migration of gefitinib-resistant lung cancer PC-9/GR cells by regulating epithelial-mesenchymal transition via PI3K/Akt/mTOR pathway
    SUI Yuxia, ZHUANG Jie, ZHUANG Min, HUANG Gui
    2022, 27(6):  614-621.  doi:10.12092/j.issn.1009-2501.2022.06.003
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    AIM: To study the effect and mechanism of Delicaflavone on migration and invasion of gefitinib-resistant lung cancer cell line PC-9/GR.  METHODS: MTT assay was used to detect cell viability. Transwell and scratch assays were used to detect cell invasion and migration abilities. Western blotting was used to detect the expressions of MMP-9, MMP-2, E-cadherin, N-cadherin, Vimentin and PI3K/Akt/mTOR pathway-related proteins in PC-9/GR cells. RESULTS: Compared with control group, 20 mg/L Delicaflavone could significantly inhibit the viability of PC-9/GR cells for 24 h (P<0.05), while Delicaflavone below 10 mg/L had no significant effect on cell proliferation. The number of invasive cells and migrated cells were decreased significantly by Delicaflavone in a concentration-dependent way (P<0.05 and P<0.01). Delicaflavone could concentration-dependently reduce the expression of MMP-9, MMP-2, N-cadherin, vimentin (P<0.01), meanwhile up-regulate the expression of E-cadherin (P<0.01). In addition, Delicaflavone also decreased the expression of p-PI3K, p-Akt and p-mTOR in a concentration-dependent manner (P<0.01). CONCLUSION: Delicaflavone can inhibit the migration and invasion of PC-9/GR cells by regulating epithelial-mesenchymal transition via PI3K/Akt/mTOR pathway.
    Osthole attenuates diabetes-induced renal injury by regulating NF-κB and p38/MAPK pathway mediated inflammatory responses
    JIN Yiyi, ZHOU Keting, YANG Chengcheng, XU Ping, ZHU Suyan
    2022, 27(6):  622-631.  doi:10.12092/j.issn.1009-2501.2022.06.004
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    AIM: To investigate the therapeutic effects of oral osthole on streptozotocin (STZ)-induced type 1 diabetes mellitus(T1DM) mice and explore its internal mechanism. METHODS: The diabetes model induced by STZ was established. Mice were randomly divided into control group, STZ model group, STZ+osthole group (20 mg/kg). Body weight, blood glucose, urine protein, blood urea nitrogen and creatinine were observed to detect renal function. The degree of renal tissue damage was detected by H&E staining and PAS staining, and the degree of renal fibrosis was detected by Sirius Red staining. CD68 and F4/80 immunofluorescence staining was used to observe the infiltration of macrophages in kidney tissue. The mRNA expressive levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) in renal tissue were detected by RT-qPCR. The protein expressive levels of phospho-NF-κB p65, NF-κB p65, IκBα, phospho-IκBα, phospho-p38 and p38 were detected by Western blot in renal tissue. RESULTS: Compared with the STZ model group, the levels of urinary protein, blood urea nitrogen, creatinine were significantly decreased after osthole treatment (P<0.05 or P<0.01). The renal structure disorder, mesangial matrix area, collagen fiber accumulation, and macrophage infiltration were significantly improved (P<0.05 or P<0.01). The expression of mRNA of pro-inflammatory cytokines TNF-α and IL-6 were significantly decreased (P<0.05 or P<0.001). The expression of phospho-NF-κB p65, phospho-IκBα and phospho-p38 were significantly down-regulated (P<0.05 or P<0.01), while the protein expression level of NF-κB p65, IκBα was up-regulated (P<0.05). CONCLUSION: Osthole has a protective effect on kidney injury caused by diabetes and inhibits NF-κB and p38/MAPK signaling pathway.
    Swimming improves renal function of diabetic mice by promoting autophagy
    WANG Zhen, QUAN Haiyan, HONG Chenliang, YUAN Lijialong, QIN Xuping
    2022, 27(6):  632-638.  doi:10.12092/j.issn.1009-2501.2022.06.005
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    AIM: To study the protective effect and mechanism of swimming on kidney of diabetic mice.  METHODS: The mice were randomly divided into normal control group, normal swimming group, type 2 diabetes mellitus (T2DM) mice model group, diabetic swimming group and metformin group. T2DM model was established by streptozotocin (STZ) method. The mice in normal swimming group and diabetic swimming group were given swimming exercise (1 h a day), and the metformin group were given metformin (200 mg/kg) by gavage once a day for 7 weeks. Fasting blood glucose and serum insulin were measured and insulin resistance index was calculated. The contents of uric acid, urea and creatinine in serum were determined. The ratio of renal mass to body mass was calculated, and the pathological changes of renal tissues were observed. The relative expressions of autophagy related proteins LC3 and P62 in renal tissues were detected by Western blot. RESULTS: Compared with normal control group, insulin resistance index and renal mass/body mass ratio in model group were significantly increased. Serum uric acid, urea and creatinine levels increased, and glomerular pathological changes were obvious. LC3II/LC3I ratio decreased significantly. The expression of P62 was significantly increased. Compared with model group, insulin resistance index and renal mass/body mass ratio in diabetic swimming group were significantly decreased. The contents of serum uric acid, urea and creatinine decreased, and the pathological changes of glomerular were alleviated. LC3II/LC3I ratio increased significantly. The expression of P62 decreased significantly (P even <0.05). CONCLUSION: Swimming protects the kidney injury of T2DM mice, and its mechanism may be related to promoting the autophagy process of renal tissue.
    Effects of intestinal flora disturbance on postoperative cognitive dysfunction in patients with inhalation anesthesia
    CHEN Jian, LAN Yu, WU Yong, SHEN Boxiong
    2022, 27(6):  639-644.  doi:10.12092/j.issn.1009-2501.2022.06.006
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    AIM: To explore the effect of intestinal flora disturbance on postoperative cognitive dysfunction in patients with inhalation anesthesia by using propensity score matching method.  METHODS: Patients received inhalation anesthesia of patients between January 2018 and December 2021 in our hospital were included in the study. 91 cases of postoperative cognitive dysfunction patients as cognitive impairment group, 85 cases of postoperative cognitive dysfunction patients as control group. Propensity score matching method was used to compare the clinical data and bacterial DNA, which was extracted from the stool samples of the two groups before surgery. And 16S rRNA sequencing was performed to analyze the differences of intestinal flora between the two groups. RESULTS: A total of 20 pairs of patients were successfully matched between the two groups. There was no significant difference in age, gender and other general information between the two groups (P>0.05). PCoA analysis showed that although there was some overlap in the PCoA plot of stool samples from the two groups, the PCoA scatter plot showed significant differences between the two groups. LEfse multistage species difference discriminant analysis showed that at the genus level, the abundance of 6 bacteria genera was higher in the cognitive impairment group. The intestinal bacillus genus, MAO spirillum, thick wall bacteria door, clostridium, neisseria bacterium, neisseria bacteria genera abundance increased in the cognitive impairment group, majorly the klebsiella bacillus clostridium, platts bacteria and enterobacteriaceae, mesh, wool spirillum, addicted to bile bacteria genera, door deformation, clostridium, enterobacteriaceae bacteria enriched, etc. CONCLUSION: Cognitive dysfunction in patients with inhalation anesthesia is related to intestinal flora disorder, which is mainly manifested by the enrichment of Bacteria such as Leiborella and Prevotella.
    Study on the factors affecting the steady-state blood concentration of tacrolimus in patients with autoimmune diseases
    DU Wenpeng, AO Jiangen, TAO Yi, WU Guansheng, HE Jiake
    2022, 27(6):  645-651.  doi:10.12092/j.issn.1009-2501.2022.06.007
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    AIM: To investigate the effects of age, gender, duration of medication and combined medication on the steady-state blood concentration of tacrolimus in patients with autoimmune diseases, and to establish the reference range of steady-state blood concentration of tacrolimus in combination with liver and kidney function, so as to provide theoretical basis for clinical individual medication.  METHODS: A total of 107 patients with autoimmune diseases treated with tacrolimus in the department of rheumatology and immunology of our hospital from August 2017 to June 2021 were included. Their gender, age, dose, drug combination, blood concentration, and liver and kidney function were statistically analyzed by SPSS 22.0 statistical software. RESULTS: In the treatment of autoimmune diseases with tacrolimus, there was statistical significance in the blood concentration of different genders (P<0.05), but there was no statistical significance in the blood concentration of different ages (P>0.05) and a statistically significant difference in the dosage of tacrolimus (P<0.05), the duration of medication did not affect the effective dose, target blood concentration, liver and kidney functions. There was a weak correlation between tacrolimus dose and blood concentration (r=0.115, P=0.047). When the blood concentration of tacrolimus ranged from 4.20 to 9.48 ng/mL, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and urea increased significantly. When tacrolimus blood concentration ranged from 0.08 to 4.20 ng/mL, there was no significant difference in serum creatinine, AST, ALT, albumin, total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL). CONCLUSION: Tacrolimus is used for the treatment of autoimmune diseases, and the blood concentration varies greatly among individuals. To avoid the risk of potential damage to liver and kidney function. It is recommended that clinicians control the blood concentration at 0.08-4.20 ng/mL, and adjust the dose and optimize the dose according to the patient's gender, age, and clinical efficacy.
    Distribution of CYP2C9*3 and VKORC1-1639G>A gene polymorphism in Anhui Han population and their influence on the stable dose of warfarin
    WU Yuanzhu, LIU Jun, YANG Kui, PENG Jing, LUAN Jiajie, WEI Jun, ZHANG Dafa, SONG Shuai, YUAN Xiaolong, WANG Zhongfang, ZHANG Nianbao, XIE Dan, JIANG Peng, FAN Jie
    2022, 27(6):  652-659.  doi:10.12092/j.issn.1009-2501.2022.06.008
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    AIM: To study the distribution of CYP2C9*3 and VKORC1-1639G>A gene polymorphism in Han population in Anhui province and their influence on the stable dose of warfarin. METHODS: The blood samples of 1 169 patients from 6 tertiary general hospitals in 5 areas of Anhui province from January 2020 to December 2021 were selected, the genotype of CYP2C9*3 and VKORC1-1639G>A was detected by fluorescent staining in situ hybridization technique. RESULTS: The distribution of CYP2C9*3 genotypes in 1 169 patients: the frequencies of AA, AC and CC genes were 90.16%, 9.24% and 0.60%, respectively; The distribution of VKORC1 genotype: the frequencies of AA, AG and GG genes were 84.26%, 14.71% and 1.03% respectively; There was no significant difference between the two genotypes in gender, age and regional distribution (P>0.05). The average daily warfarin dose of CYP2C9*3 AA genotype in 755 patients with stable warfarin dose was (3.02±0.59) mg/d, which was significantly higher than patients with AC genotype and CC genotype; The average daily warfarin dose of patients with VKORC1-1639AA  genotype was (2.72±0.40) mg/d, which was significantly lower than that of patients with AG genotype and GG genotype (P<0.05). And the difference was statistically significant (P<0.05); There are significant differences in gender, age and clinical diagnosis between patients with stable dose of warfarin and those without stable dose (P<0.05). CONCLUSION: CYP2C9 and VKORC1 genotypes are associated with the stable dose of warfarin. Clinical anticoagulation therapy guided by CYP2C9 and VKORC1 genotypes can provide guidance for individualized medication of warfarin.
    Effective dose of esketamine for prevention on propofol injection pain in painless abortion
    SHEN Yanping, YIN Lijun, ZHUANG Wenming, YAN Haiya
    2022, 27(6):  660-664.  doi:10.12092/j.issn.1009-2501.2022.06.009
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    AIM: To investigate the effective dose of esketamine for prevention on propofol injection pain in painless abortion.  METHODS: From November 2021 to December 2021, thirty patients undergoing painless abortion, aged 20 to 40 years old, ASA physical status Ⅰ or Ⅱ, BMI 19-26 kg/m2 were enrolled. The experiment was used with a modified Dixon up and down method. The initial dose of esketamine was 0.2 mg/kg, and the dose gradient of esketamine in adjacent patients was 0.02 mg/kg. When propofol injection pain was positive, the next patient was given a high first-order dose, otherwise a low first-order dose was used, and the experiment ended when the 7th crossovers were appeared. The ED50, ED95 and the corresponding 95% confidence interval (CI) of esketamine were calculated by Probit analysis. The values of MAP, SpO2 and HR were recorded before injection (T0), after esketamine injection (T1), after propofol injection (T2) and after operation (T3). At the same time, the adverse reactions such as awakening time, nausea and vomiting, delirium and abnormal vision were observed and recorded. RESULTS: The ED50, ED95 and 95%CI of esketamine for prevention on propofol injection pain were 0.135 (0.116-0.149) mg/kg and 0.170 (0.153-0.252) mg/kg. Compared with T0, the value of MAP at T1 was significantly higher, the value of MAP and SpO2 at T2 were significantly lower (P<0.05), and the recovery time was (7.2±3.1) min. No adverse reactions such as nausea and vomiting, postoperative agitation, delirium and abnormal vision occurred in all patients. CONCLUSION: The ED50 and ED95 of esketamine for prevention on propofol injection pain were 0.135 mg/kg and 0.170 mg/kg, respectively. Low dose of esketamine can effectively prevent the pain of propofol injection during painless abortion and maintain the stability of hemodynamics.
    Retrospectively analysis of the effect of low-dose aspirin on primary prevention of non-fatal myocardial infarction and cerebral infarction in patients with type 2 diabetes mellitus
    ZENG Xiaofan, XU Yiqi, LIU Shu, WU Qian, LI Zibao, HE Junjun, JIN Yuelong, ZHAO Yongli, HE Chunling, GAO Jialin
    2022, 27(6):  665-671.  doi:10.12092/j.issn.1009-2501.2022.06.010
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    AIM: To investigate the effect of low-dose aspirin on primary prevention of non-fatal myocardial and cerebral infarction in patients with type 2 diabetes mellitus.  METHODS: From January 2015 to December 2016,40-90 years old patients with type 2 diabetes were treated in the Department of Endocrinology of Yijishan Hospital of Wannan Medical College for more than 2 times (the interval of hospitalization was more than 3 months) , we use the hospital's his system to search out-patient and in-patient files, patients were divided into aspirin group and non-aspirin group according to the use of low-dose aspirin within 1 year after the first visit, the basic data of the first visit were collected: name, sex, age, course of diabetes, systolic and diastolic blood pressure, patients were recorded for laboratory markers including fasting blood glucose, glycated hemoglobin, triglyceride, total cholesterol, Low-density lipoprotein, high-density lipoprotein, creatinine, and platelets, complications such as hypertension, coronary heart disease, atrial fibrillation, hyperlipidemia, diabetic nephropathy and arteriosclerosis were recorded. A Chi square test and a Cox proportional hazard model were used to compare baseline data and cerebrovascular disease after the first use of aspirin. RESULTS: Of the 4 176 patients, 2 137 were type 2 diabetes, 417 were eligible for admission, including 198 males, 219 females, 224 aspirin users and 193 non-users. There was no significant difference in the incidence of cerebral infarction between the aspirin group and the non-aspirin group (χ2=0.820, P=0.365). The incidence of non-fatal myocardial infarction was lower than that of the aspirin non-aspirin group (χ2=10.099, P=0.01) , the incidence of massive hemorrhage was significantly higher than that of aspirin-free group χ2=5.425, P=0.020) . In a subgroup analysis of aspirin use, patients younger than 60 years of age had a lower incidence of ischemic stroke (cerebral infarction) and a risk ratio of 0.428 (95%CI: 0.255-0.719, P=0.001) compared with patients older than 60 years of age, the incidence of cerebral infarction was higher in female patients with a risk ratio of 1.574 (95%CI: 1.018-2.434, P=0.041). CONCLUSION: In this study of patients with type 2 diabetes, low-dose aspirin reduced the incidence of nonfatal myocardial infarction but had no significant effect on the incidence of nonfatal ischemic stroke, and significantly increase the incidence of major bleeding events, we should reconsider the use of low-dose aspirin as a potential benefit of nonfatal cerebral infarction in patients with type 2 diabetes.
    Roles of indoxyl sulfate in complications of chronic kidney disease
    ZHU Xinru, HUANG Xin
    2022, 27(6):  672-679.  doi:10.12092/j.issn.1009-2501.2022.06.011
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    Chronic kidney disease is a global public health problem, and its occurrence and development are closely related to the exposure of uremic toxins in vivo. Indoxyl sulfate is one of protein-bound enterogenous uremic toxin, it significantly accumulates in patients with chronic kidney disease as renal function declines. Indoxyl sulfate not only promotes the progression of chronic kidney disease, but also induces pathological changes in other tissues and organs, causing complications in other organs related to chronic kidney disease. This article mainly reviews the effect of indoxyl sulfate on blood vessels, muscle, skeleton and brain and their mechanisms, and summarizes chronic kidney disease treatment by clearing indoxyl sulfate.
    Effects of Chinese patent medicine for activating blood circulation on cardiac repair after myocardial infarction
    CHEN Xi, LI Yongjun
    2022, 27(6):  680-688.  doi:10.12092/j.issn.1009-2501.2022.06.012
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    Myocardial infarction (MI) is a cardiovascular disease with high morbidity and mortality, which seriously endangers human health. Poor ways of repair after MI may damage people's life quality, therefore scientists have been committed to exploring the way of myocardial repair after MI to strive for a better prognosis of these patients. Chinese patent medicines for blood circulation activation have a long history of use in treatment of MI, where they have been shown to attenuate myocardial injury after MI and promote cardiac repair with multiple targets, links and pathways. This review focuses on a few representative Chinese patent medicines for MI and summarizes their pharmacological effects and clinical research in cardiac repair following MI, effectively providing scientific foundation on treating MI with Chinese patent medicines.
    Research progress on the imbalance of coagulation and fibrinolysis system and the pathogenesis and treatment of idiopathic pulmonary interstitial fibrosis
    SUN Ying, YU Qin
    2022, 27(6):  689-695.  doi:10.12092/j.issn.1009-2501.2022.06.013
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    Idiopathic pulmonary interstitial fibrosis (IPF) is a progressive interstitial lung disease. Its prognosis is worse than that of many cancers. Its pathogenesis is complex and unclear. The imbalance of coagulation system and fibrinolysis system was confirmed in both animal models of pulmonary fibrosis and patients with IPF. This paper expounds the possible injury mechanism of the imbalance of coagulation and fibrinolysis system in IPF, and provides a new idea for the treatment of IPF. 
    Research progress of microRNA in diagnosis and treatment of prostate cancer
    DING Hao, GAO Zhenhua, ZHENG Yun
    2022, 27(6):  696-708.  doi:10.12092/j.issn.1009-2501.2022.06.014
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    Prostate cancer (PCa) is an epithelial malignancy that occurs in the prostate tissue and is the second most common cancer in men after lung cancer, affecting millions of men worldwide. MicroRNA (miRNA) is a non-coding small RNA of length 20-22nt that regulates gene expression post-transcriptionally. miRNAs are involved in the regulation of almost all important biological life processes such as cell cycle progression, cell proliferation, cell apoptosis, and cell migration. Recently, more and more studies have shown that miRNAs are involved in the occurrence of various human tumors including PCa. This review summarizes the current research progress of PCA-related miRNAs, and analyzes the role of malregulated miRNAs in the pathogenesis, diagnosis and treatment of PCa. In addition, the role of miRNA in the diagnosis and treatment of castration-resistant prostate cancer (CRPC) is emphasized.
    Integrins targeting αv are used as drug targets for pulmonary fibrosis
    LIU Nanyu, YUE Hongmei, SONG Peipei, WEI Jifang, WEI Yaqian, XIE Yingying, WANG Jiaqi
    2022, 27(6):  709-714.  doi:10.12092/j.issn.1009-2501.2022.06.015
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    IPF is a chronic progressive interstitial lung disease of unknown etiology and poor prognosis, and despite receive treatment, most patients consideration are likely to progress or worsen. Integrins are heterodimer cell surface proteins that are promising therapeutic targets for intervention in pulmonary fibrosis. Alphav integrins are central to the development of fibrosis because they activate latent TGF-β, a known pro-fibrosis cytokine. The alphav subunit may form heterodimers with the β1, β3, β5, β6, or β8 subunits, one or more of which are essential for the development of pulmonary fibrosis, but their relative importance is unclear. This review summarizes the knowledge of the association of pulmonary fibrosis with alpha-val-integrins, as well as emerging preclinical studies and clinical trials of alpha-fibrosis inhibitors.
    Research progress on the relationship between melatonin and idiopathic pulmonary fibrosis
    LI Xueheng, LI Long
    2022, 27(6):  715-720.  doi:10.12092/j.issn.1009-2501.2022.06.016
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    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fibrotic lung disease. The etiology is unclear and the pathogenesis is not completely clear. At present, there is no curable drug. Melatonin (MT) is a neurohormone produced and released by the pineal gland of vertebrates.Many studies have shown that melatonin has anti fibrosis effect, which can inhibit the development of pulmonary fibrosis by reducing oxidative stress, inhibiting inflammatory response, inhibiting epithelial mesenchymal transformation, anti apoptosis and regulating autophagy. This paper summarizes the research results of the relationship between MT and IPF in recent years, in order to provide new ideas for the clinical treatment of IPF.