Lung cancer progression alters lung and gut microbiomes and lipid metabolism.

Despite advances in medical technology, lung cancer still has one of the highest mortality rates among all malignancies. Therefore, efforts must be made to understand the precise mechanisms underlying lung cancer development. In this study, we conducted lung and gut microbiome analyses and a comprehensive lipid metabolome analysis of host tissues to assess their correlation. Alternations in the lung microbiome due to lung cancer, such as a significantly decreased abundance of Firmicutes and Deferribacterota, were observed compared to a mock group. However, mice with lung cancer had significantly lower relative abundances of Actinobacteria and Proteobacteria and higher relative abundances of Cyanobacteria and Patescibacteria in the gut microbiome. The activations of retinol, fatty acid metabolism, and linoleic acid metabolism metabolic pathways in the lung and gut microbiomes was inversely correlated. Additionally, changes occurred in lipid metabolites not only in the lungs but also in the blood, small intestine, and colon. Compared to the mock group, mice with lung cancer showed that the levels of adrenic, palmitic, stearic, and oleic (a ω-9 polyunsaturated fatty acid) acids increased in the lungs. Conversely, these metabolites consistently decreased in the blood (serum) and colon. Leukotriene B4 and prostaglandin E2 exacerbate lung cancer, and were upregulated in the lungs of the mice with lung cancer. However, isohumulone, a peroxisome proliferator-activated receptor gamma activator, and resolvin (an ω-3 polyunsaturated fatty acid) both have anti-cancer effects, and were upregulated in the small intestine and colon. Our multi-omics data revealed that shifts in the microbiome and metabolome occur during the development of lung cancer and are of possible clinical importance. These results reveal one of the gut-lung axis mechanisms related to lung cancer and provide insights into potential new targets for lung cancer treatment and prophylaxis.

Al-Sc Bonded Complexes: Synthesis, Structure, and Reaction with Benzene in the Presence of Alkyl Halide.

An alumanyl anion possessing N,N'-bis(2,6-diisopropylphenyl)-1,3-propanediamine ligand was synthesized and characterized. Transmetalation of this Al anion with diaminoscandium chloride precursors afforded the corresponding Al-Sc complexes possessing an unprecedented Al-Sc bond. The Al-Sc[N(SiMe3)2] complex underwent intramolecular C-H cleavage to form a bridged dinuclear complex with µ-hydrido and µ-methylene ligands. The Al-Sc(NiPr2)2 complex reacted with benzene in the presence of alkyl bromide to furnish a 1,4-dialuminated cyclohexadiene product with a concomitant formation of the alkyl-alkyl coupled product. Although the latter product seems to form through the radical mechanism, DFT calculations revealed an ionic mechanism involving bimetallic reaction pathways to react with alkyl bromide and benzene, which provides new insight into the chemistry of metal-metal bonded compounds.

Cardiopulmonary exercise testing for patients with anorexia nervosa: a case-control study.

PURPOSE: Patients with anorexia nervosa (AN) require appropriate nutrient therapy and physical activity management. Eating disorder treatment guidelines do not include safe, evidence-based intensity criteria for exercise. This study used cardiopulmonary exercise testing (CPX) to evaluate the exercise tolerance of patients with AN. METHODS: CPX was performed with 14 female patients with AN admitted to a specialized eating disorder unit between 2015 and 2019. Their anaerobic threshold (AT) was determined by assessing their exercise tolerance using CPX and compared with 14 healthy controls (HC). The metabolic equivalents (AT-METS) were compared when AT was reached. We examined factors related to AT (AN-AT) in the AN group, including age, body mass index (BMI), previous lowest weight, minimum BMI, past duration of BMI < 15, exercise history, and ΔHR (heart rate at the AT-resting heart rate). RESULTS: The AT of the AN group (BMI: 15.7 [Mean] ± 1.8 standard deviation [SD]) was significantly lower than that of the HC group (BMI: 19.7 ± 1.8) (AN: 10.0 ± 1.8 vs. HC: 15.2 ± 3.0 ml/kg/min, P < 0.001). AT-METS was also significantly lower in the AN group than in the HC group (AN: 2.9 ± 0.52 vs. HC: 4.4 ± 0.91, P < 0.001). AN-AT was highly influenced by ΔHR. CONCLUSIONS: This study showed that AT and AT-METS were lower in patients with AN than in HC. Patients with AN should be prescribed light-intensity aerobic exercise, and the current findings may help develop future physical management guidelines for patients with AN. LEVEL OF EVIDENCE: III: Evidence obtained from case-control analytic studies.

Rhodium-Catalyzed Acrylate Synthesis from Carbon Dioxide and Ethylene by using a Guanidine-Based Pincer Ligand: Perturbing Occupied d-Orbitals by pπ-dπ Repulsion Makes a Difference.

Rhodium-catalyzed acrylate synthesis from CO2 and ethylene was accomplished by using a guanidine-based NCN pincer ligand. The repulsion between pπ-electron of guanidine sidearms and occupied dπ orbital of rhodium center raised the level of d-electrons close to those of formerly known d8 -ruthenium catalyst, thereby promoting the metallalactone formation from carbon dioxide and ethylene. This work fills the absence of group-9 metal based catalyst for the acrylate synthesis and provides a designing approach for pincer-ligated d8 -metal catalysts to utilize pπ-dπ interaction for promoting desirable redox processes.

Clostridium butyricum enhances colonization resistance against Clostridioides difficile by metabolic and immune modulation.

Clostridioides difficile infection (CDI) represents the leading cause of nosocomial diarrhea worldwide and is associated with gut dysbiosis and intestinal damage. Clostridium butyricum MIYAIRI 588 (CBM 588) contributes significantly to reduce epithelial damage. However, the impacts of CBM 588 on antibacterial therapy for CDI are not clear. Here we show that CBM 588 enhanced the antibacterial activity of fidaxomicin against C. difficile and negatively modulated gut succinate levels to prevent C. difficile proliferation and downregulate tumor necrosis factor-α (TNF-α) producing macrophages in the colon lumina propria (cLP), resulting in a significant decrease in colon epithelial damage. Additionally, CBM 588 upregulated T cell-dependent pathogen specific immunoglobulin A (IgA) via interleukin (IL)-17A producing CD4+ cells and plasma B cells in the cLP, and Th17 cells in the cLP enhanced the gut epithelial barrier function. IL-17A and succinic acid modulations with CBM 588 enhance gut colonization resistance to C. difficile and protect the colon tissue from CDI.

Catamenial pneumothorax with partial liver herniation due to diaphragmatic laceration: a case report and literature review.

BACKGROUND: Catamenial pneumothorax is generally uncommon, with an incidence of less than 3-6% in women with spontaneous pneumothorax. As few cases of catamenial pneumothorax with diaphragmatic defect and liver herniation have been reported, this case report may be useful for understanding the cause and treatment. This case highlights the importance of the approach for liver hernia in patients with catamenial pneumothorax and endometriosis. CASE PRESENTATION: We report a case of catamenial pneumothorax in a 43-year-old woman with diaphragmatic partial liver hernia who was treated with thoracoscopic surgery. She was diagnosed with a right pneumothorax at menstruation onset. Chest computed tomography showed a nodule protruding above the right diaphragm. We performed thoracoscopic surgery to treat the persistent air leak and biopsied the nodule on the right diaphragm. There were blueberry spots on the diaphragm; the nodule was found to be the herniated liver. The diaphragmatic defect was sutured. Histological examination of the tissue near the partial prolapsed liver revealed endometrial tissue. CONCLUSIONS: It is speculated that ectopic endometrial tissue in the diaphragm will periodically necrose to become a diaphragmatic tear, which is a pathway for air to enter the thoracic cavity and eventually a herniated liver. Thoracoscopic surgery should be considered in patients with catamenial pneumothorax when a diaphragmatic lesion is suspected.

A meta-Selective C-H Alumination of Mono-Substituted Benzene by Using An Alkyl-Substituted Al Anion through Hydride-Eliminating SN Ar Reaction.

Reaction of an Al-centered anion with toluene proceeded to form C-H cleaved product with a perfect meta-selectivity and a relatively small kinetic isotope effect (KIE, kH /kD =1.51). DFT calculations suggested a two-step reaction mechanism and electronically controlled meta-selectivity arising from the electron-donating methyl group. The reaction with other mono-substituted arenes was also investigated.

Asymmetrical surface scanning registration for image-guided otologic surgery: A phantom study.

OBJECTIVE: To develop a registration procedure to achieve a higher degree of registration accuracy in image-guided otological surgery, paying particular attention to the registration centroid. METHODS: A head phantom was used to measure the target registration error (TRE) at measurement points at various depth from the surface of the head. The surface-matching registration was performed using a commercially available surgical navigation system. We registered the phantom using only one ear of either side (right 100% - left 0%, or right 0% - left 100%) or using both ears with variable ratios (right 75% - left 25%, right 50% - left 50%, or right 25% - left 75%). RESULTS: The overall TRE was the smallest when registration was performed equally on both sides. However, the TRE at 20-50 mm from the surface was the smallest when the fiducial points for the registration were collected asymmetrically at a ratio of 75:25 and weighed heavier on the operating side, and this difference was statistically significant. CONCLUSION: The accuracy of image-guided surgery can be improved by carefully planning the registration procedure without changing the procedure itself. Accurate image-guided surgery at the middle and inner ear was achieved using 75% of the point cloud for the operating side and 25% of that for the opposite side for the registration.

The inducible amphisome isolates viral hemagglutinin and defends against influenza A virus infection.

The emergence of drug-resistant influenza type A viruses (IAVs) necessitates the development of novel anti-IAV agents. Here, we target the IAV hemagglutinin (HA) protein using multivalent peptide library screens and identify PVF-tet, a peptide-based HA inhibitor. PVF-tet inhibits IAV cytopathicity and propagation in cells by binding to newly synthesized HA, rather than to the HA of the parental virus, thus inducing the accumulation of HA within a unique structure, the inducible amphisome, whose production from the autophagosome is accelerated by PVF-tet. The amphisome is also produced in response to IAV infection in the absence of PVF-tet by cells overexpressing ABC transporter subfamily A3, which plays an essential role in the maturation of multivesicular endosomes into the lamellar body, a lipid-sorting organelle. Our results show that the inducible amphisomes can function as a type of organelle-based anti-viral machinery by sequestering HA. PVF-tet efficiently rescues mice from the lethality of IAV infection.

Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis.

Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.

PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis.

Cigarette smoke (CS)-induced accumulation of mitochondrial damage has been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Mitophagy plays a crucial role in eliminating damaged mitochondria, and is governed by the PINK1 (PTEN induced putative protein kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway. Although both increased PINK1 and reduced PRKN have been implicated in COPD pathogenesis in association with mitophagy, there are conflicting reports for the role of mitophagy in COPD progression. To clarify the involvement of PRKN-regulated mitophagy in COPD pathogenesis, prkn knockout (KO) mouse models were used. To illuminate how PINK1 and PRKN regulate mitophagy in relation to CS-induced mitochondrial damage and cellular senescence, overexpression and knockdown experiments were performed in airway epithelial cells (AEC). In comparison to wild-type mice, prkn KO mice demonstrated enhanced airway wall thickening with emphysematous changes following CS exposure. AEC in CS-exposed prkn KO mice showed accumulation of damaged mitochondria and increased oxidative modifications accompanied by accelerated cellular senescence. In vitro experiments showed PRKN overexpression was sufficient to induce mitophagy during CSE exposure even in the setting of reduced PINK1 protein levels, resulting in attenuation of mitochondrial ROS production and cellular senescence. Conversely PINK1 overexpression failed to recover impaired mitophagy caused by PRKN knockdown, indicating that PRKN protein levels can be the rate-limiting factor in PINK1-PRKN-mediated mitophagy during CSE exposure. These results suggest that PRKN levels may play a pivotal role in COPD pathogenesis by regulating mitophagy, suggesting that PRKN induction could mitigate the progression of COPD. Abbreviations: AD: Alzheimer disease; AEC: airway epithelial cells; BALF: bronchoalveolar lavage fluid; AKT: AKT serine/threonine kinase; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; COPD: chronic obstructive pulmonary disease; CS: cigarette smoke; CSE: CS extract; CXCL1: C-X-C motif chemokine ligand 1; CXCL8: C-X-C motif chemokine ligand 8; HBEC: human bronchial epithelial cells; 4-HNE: 4-hydroxynonenal; IL: interleukin; KO: knockout; LF: lung fibroblasts; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PCD: programmed cell death; PFD: pirfenidone; PIK3C: phosphatidylinositol-4:5-bisphosphate 3-kinase catalytic subunit; PINK1: PTEN induced putative kinase 1; PTEN: phosphatase and tensin homolog; RA: rheumatoid arthritis; ROS: reactive oxygen species; SA-GLB1/ß-Gal: senescence-associated-galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SNP: single nucleotide polymorphism; TNF: tumor necrosis factor.

Perioperative outcomes of thoracoscopic lung resection requiring a long operative time.

OBJECTIVES: Difficult thoracoscopic surgery sometimes requires a long operative time. It is unclear whether patients benefit from such thoracoscopic surgeries. We investigated whether thoracoscopic surgery for difficult cases contributed to improvements in perioperative outcomes. METHODS: We retrospectively reviewed cases of anatomical lung resection with thoracoscopic surgery, including conversion to thoracotomy, between January 2006 and December 2016 and compared patient demographics and perioperative outcomes of the long (≥360 min) and the normal operative time groups (<360 min). RESULTS: One hundred and seventy-six patients were in the long operative time group and 655 patients were in the normal operative time group. The long operative time group had more male patients, more progressive clinical stages, bilobectomy or pneumonectomy, conversion to thoracotomy and more blood loss than the normal operative time group. The long operative time group had higher rates of postoperative complications and longer hospital stay (30% vs 16%, P < 0.001 and 9 ± 9 days vs 7 ± 8 days, P < 0.001; respectively). Multivariate analysis showed that in the first half of the operative period, chronic obstructive pulmonary disease and bilobectomy or pneumonectomy were independent predictive factors for postoperative complications. The long operative time as a factor was close to statistical significance (odds ratio 1.689, P = 0.079) unlike the elective conversion to thoracotomy (odds ratio 0.784, P = 0.667) and emergency conversion to thoracotomy (odds ratio 0.938, P = 0.924). CONCLUSIONS: In conclusion, when difficult cases are encountered, conversion to thoracotomy should be considered by surgeons if continuation of thoracoscopic surgery increases the operative time.

Impact of the introduction of thoracoscopic lobectomy for non-small cell lung cancer: a propensity score-matched analysis.

BACKGROUND: The present study evaluated the impact of the introduction of thoracoscopic lung lobectomy (TL) for non-small cell lung cancer at our institution. METHODS: This study retrospectively compared surgical and oncological outcomes in the period before and after the introduction of TL for non-small cell lung cancer. Propensity score-matched analysis was performed with respect to baseline patient variables and tumor characteristics. RESULTS: Patients were divided into two groups: those who underwent lung lobectomy in the period before (BI group, n=261) and after (AI group, n=261) the introduction of TL. The proportion of TLs at our institution increased from 1.3% in the BI group to 93% in the AI group. The AI group experienced a longer duration of surgery, lesser intraoperative blood loss, and a significantly shorter postoperative hospital stay (POHS). There were no significant differences in postoperative complications between the two groups. The median follow-up period was 50 months in both groups. No significant differences were observed between the BI and AI groups with respect to 5-year overall survival (OS) (76.1% and 71.7%, respectively; P=0.1973) and disease-free survival (DFS) (67.6% and 66.1%, respectively; P=0.4071). On multivariate analysis, pathological N1-2 status was an independent predictor of survival. AI group and TL showed no independent association with survival. CONCLUSIONS: The introduction of TL represented a positive change at our institution owing to decreased invasiveness and oncological equivalence of the surgical treatment for non-small cell lung cancer.

Vitamin D Supplementation and Survival of Patients with Non-small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non-small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869).Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, <20 ng/mL vs. high, ≥20 ng/mL). Polymorphisms of vitamin D receptor (VDR) and vitamin D-binding protein (DBP) and survival were also examined.Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment.Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089-97. ©2018 AACR.

A zwitterionic aluminabenzene-alkylzirconium complex having half-zirconocene structure: synthesis and application for additive-free ethylene polymerization.

An aluminabenzene-alkylzirconium complex having a half-zirconocene structure was synthesized. X-ray crystallographic analysis of this complex revealed a zwitterionic structure consisting of cationic alkylzirconium chloride and four-coordinated aluminate. In the presence of a catalytic amount of this complex, ethylene polymerization could proceed without any additives to form ultra-high molecular weight polyethylene.

Effect of comorbidities on long-term outcomes after thoracoscopic surgery for stage I non-small cell lung cancer patients with chronic obstructive pulmonary disease.

BACKGROUND: We assessed how the severity of chronic obstructive pulmonary disease (COPD) and other comorbidities affect long-term survival after thoracoscopic lung resection for c-stage I non-small cell lung cancer (NSCLC). METHODS: Patients with c-stage I NSCLC who underwent thoracoscopic lung resection at our hospital between 2006 to 2014 were retrospectively analyzed. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric grades were used to classify the severity of COPD, and comorbidity was classified according to the Charlson comorbidity index (CCI). Various outcomes were assessed and compared. RESULTS: The cohort comprised 404 patients with NSCLC, of whom 133 were diagnosed with COPD (51 as GOLD 1, 79 as GOLD 2, and 3 as GOLD 3) and 271 were diagnosed without COPD. The 5-year overall survival (OS) rates were 86.0%, 80.2%, and 71.1% for the non-COPD, GOLD 1, and GOLD 2/3 groups, respectively (P=0.0221); the corresponding 5-year disease-specific survival (DSS) rates were 91.7%, 86.9%, and 85.1% (P=0.2136). Univariate analysis indicated that sex, smoking status, pathology, COPD severity, CCI, and pathological stage were associated with OS, and multivariate analysis confirmed the association with CCI and pathological stage. Postoperative complications were significantly more frequent in the GOLD 1 (21.5%) and GOLD 2/3 (26.8%) groups than in the non-COPD group (12.1%) (P=0.0040). CONCLUSIONS: Following thoracoscopic surgery (TS) for NSCLC, patients with COPD had a poorer OS than patients without COPD. However, the CCI and not the COPD severity was the independent prognostic factor for OS. Comorbidities adversely affected long-term survival of patients with stage I NSCLC and COPD after TS, and the same effect can be oncologically expected regardless of the COPD severity.

Preoperative simulation unveiled undetected surgical difficulties in a case of cochlear implantation.

We herein report a case in which extensive preparation changed a difficult-to-treat patient into an easy one. We performed a revision cochlear implantation on a patient whose first procedure had been aborted due to unidentified difficulties. During a series of thorough three-dimensional simulations, we found that the patient in question had a normal cochlea but the cochlea was placed in an unusual position and orientation. This condition is difficult to detect on standard preoperative radiographic images. Through this simulation, we were able to propose a surgical plan to avoid making the same mistakes as the first surgeon. We present this case not as a rare difficult case of an unfortunate patient but instead emphasise the importance of performing surgical simulation and looking for non-obvious difficulties. This case is an example of the success that can be achieved with such extensive preparation.

Surgical and oncological outcomes of thoracoscopic thymectomy for thymoma.

Thymoma remains the most common primary anterior mediastinal neoplasm. Surgical resection remains central to the treatment of thymoma, with thoracoscopic thymectomy (TT) being increasingly performed. This present review article aimed to summarize current studies comparing TT and open thymectomy (OT). Recently, most patients with Masaoka stage I-II thymoma have been receiving TT. This procedure is associated with a significantly shorter post-operative hospital stay, decreased intraoperative blood loss, and fewer complications compared with OT. Recurrence rates of thymoma after TT range from 0% to 6.7%, and the 5-year disease-free survival (DFS) ranges from 83.3% to 96%. The oncological outcomes of TT are comparable to that of OT. Masaoka stage and the World Health Organization (WHO) type classification are valuable predictors of the prognosis of thymoma; hence, the optimal treatment for thymoma should be performed according to these two. TT is less invasive, with equivalent oncological outcomes, when compared with the OT. Minimally invasive surgery including TT for stage I-II thymomas is becoming the mainstay of therapy.

Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy.

BACKGROUND: Pirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. METHODS: Transforming growth factor-ß (TGF-ß)-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice. RESULTS: We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-ß. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. CONCLUSIONS: These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.