Faculty Profiles - SAKAMOTO Koji

Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice Reviewed International journal

Christine K. Wong, Candice A. Smith, Koji Sakamoto, Naftali Kaminski, Jonathan L. Koff, Daniel R. Goldstein

JOURNAL OF IMMUNOLOGY Vol. 199 ( 3 ) page： 1060 - 1068 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC IMMUNOLOGISTS

Influenza viral infections often lead to increased mortality in older people. However, the mechanisms by which aging impacts immunity to influenza lung infection remain unclear. We employed a murine model of influenza infection to identify these mechanisms. With aging, we found reduced numbers of alveolar macrophages, cells essential for lung homeostasis. We also determined that these macrophages are critical for influenza-induced mortality with aging. Furthermore, aging vastly alters the transcriptional profile and specifically downregulates cell cycling pathways in alveolar macrophages. Aging impairs the ability of alveolar macrophages to limit lung damage during influenza infection. Moreover, aging decreases alveolar macrophage phagocytosis of apoptotic neutrophils, downregulates the scavenging receptor CD204, and induces retention of neutrophils during influenza infection. Thus, aging induces defective phagocytosis by alveolar macrophages and increases lung damage. These findings indicate that therapies that enhance the function of alveolar macrophages may improve outcomes in older people infected with respiratory viruses.

DOI： 10.4049/jimmunol.1700397

Modified mesenchymal stem cells using miRNA transduction alter lung injury in a bleomycin model Reviewed International journal

Luai Huleihel, Jacobo Sellares, Nayra Cardenes, Diana Alvarez, Rosa Faner, Koji Sakamoto, Guoying Yu, Maria G. Kapetanaki, Naftali Kaminski, Mauricio Rojas

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Vol. 313 ( 1 ) page： L92 - L103 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

Although different preclinical models have demonstrated a favorable role for bone marrow-derived mesenchymal stem cells (B-MSC) in preventing fibrosis, this protective effect is not observed with late administration of these cells, when fibrotic changes are consolidated. We sought to investigate whether the late administration of B-MSCs overexpressing microRNAs (miRNAs) let-7d (antifibrotic) or miR-154 (profibrotic) could alter lung fibrosis in a murine bleomycin model. Using lentiviral vectors, we transduced miRNAs (let-7d or miR-154) or a control sequence into human B-MSCs. Overexpression of let-7d or miR-154 was associated with changes in the mesenchymal properties of B-MSCs and in their cytokine expression. Modified B-MSCs were intravenously administered to mice at day 7 after bleomycin instillation, and the mice were euthanized at day 14. Bleomycin-injured animals that were treated with let-7d cells were found to recover quicker from the initial weight loss compared with the other treatment groups. Interestingly, animals treated with miR-154 cells had the lowest survival rate. Although a slight reduction in collagen mRNA levels was observed in lung tissue from let-7d mice, no significant differences were observed in Ashcroft score and OH-proline. However, the distinctive expression in cytokines and CD45-positive cells in the lung suggests that the differential effects observed in both miRNA mice groups were related to an effect on the immunomodulation function. Our results establish the use of miRNA-modified mesenchymal stem cells as a potential future research in lung fibrosis.

DOI： 10.1152/ajplung.00323.2016

Progression of mean pulmonary arterial pressure in idiopathic pulmonary fibrosis with mild to moderate restriction Reviewed International journal

Ryo Teramachi, Hiroyuki Taniguchi, Yasuhiro Kondoh, Masahiko Ando, Tomoki Kimura, Kensuke Kataoka, Atsushi Suzuki, Taiki Furukawa, Koji Sakamoto, Yoshinori Hasegawa

RESPIROLOGY Vol. 22 ( 5 ) page： 986 - 990 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Background and objectiveElevation of mean pulmonary arterial pressure (MPAP) is associated with poor prognosis in patients with idiopathic pulmonary fibrosis (IPF), yet the progression of MPAP in patients with IPF has not been sufficiently elucidated. We evaluated serial changes in MPAP and its determinants in patients with IPF with mild to moderate restriction.
MethodsWe retrospectively reviewed patients with IPF who underwent initial evaluations including right heart catheterization (RHC) in our institute from May 2007 to December 2013 with follow-up RHC at least 1year later. Patients with forced vital capacity (FVC)<50% predicted or those with pulmonary artery wedge pressure>15mm Hg were excluded.
ResultsA total of 95 patients were included. Median follow-up time of second RHC was 1.8years. MPAP increased significantly at follow-up (from 16.8 to 20.2mm Hg; P<0.001), and annual change in MPAP (MPAP) was 1.8mm Hg/year. In multiple regression analysis, the lowest oxygen saturation (SpO(2) ) at 6-min walk test (6MWT) was an independent predictor of MPAP. When adjusted for age, sex, baseline MPAP and FVC % predicted, MPAP was a significant predictor of mortality (hazard ratio: 1.21; P=0.001).
ConclusionMPAP was significantly associated with desaturation in the 6MWT, and with increased mortality in patients with IPF with mild to moderate restriction.
We reviewed patients with idiopathic pulmonary fibrosis with mild to moderate restriction and showed that mean pulmonary arterial pressure (MPAP) was progressive. The lowest oxygen saturation (SpO(2) ) in the 6-min walk test at baseline was an independent predictor of annual change in MPAP.

DOI： 10.1111/resp.12986

COPD Assessment Test for measurement of health status in patients with idiopathic pulmonary fibrosis: A cross-sectional study. Reviewed

Matsuda T, Taniguchi H, Ando M, Kondoh Y, Kimura T, Kataoka K, Sakamoto K, Suzuki A, Furukawa T, Hasegawa Y

Respirology (Carlton, Vic.) Vol. 22 ( 4 ) page： 721-727 2017.5

Soluble thrombomodulin in bronchoalveolar lavage fluid is an independent predictor of severe drug-induced lung injury Reviewed International journal

Atsushi Suzuki, Hiroyuki Taniguchi, Yasuhiro Kondoh, Masahiko Ando, Naohiro Watanabe, Tomoki Kimura, Kensuke Kataoka, Toshiki Yokoyama, Koji Sakamoto, Yoshinori Hasegawa

RESPIROLOGY Vol. 22 ( 4 ) page： 744 - 749 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Background and objectiveDrug-induced lung injury (DLI) can result from a vast number of agents, and sometimes presents findings similar to those of acute respiratory distress syndrome (ARDS). Previous studies have reported that circulating levels of soluble thrombomodulin (TM) reflect endothelial injuries, which play key roles in the development of ARDS. We hypothesized that endothelial injuries are an important aspect of pathogenesis in severe DLI. The primary aim of this study was to examine the associations between soluble TM and disease severity in DLI patients.
MethodsOf the 2580 patients who underwent a bronchoalveolar lavage (BAL) procedure at Tosei General Hospital between May 2007 and February 2015, we retrospectively analysed the data of 68 DLI patients. Soluble TM in plasma and BAL fluid (BALF), and other biomarkers were included in our analysis.
ResultsAt the time of diagnosis, 39 patients (57%) had respiratory failure (partial pressure of oxygen/inspiratory oxygen fraction ratio, PaO2 /FiO(2) ratio<300). There was a significant negative linear correlation between the PaO2 /FiO(2) ratio and soluble TM in BALF (r=-0.448, P<0.001). In a stepwise multiple regression analysis, soluble TM in BALF and surfactant protein D (SP-D) were the only independent determinants of the PaO2 /FiO(2) ratio. Additionally, in a multivariate logistic regression model, soluble TM in BALF (adjusted OR (aOR): 7.48, 95% CI: 1.60-34.98) and SP-D (aOR: 5.31, 95% CI: 1.40-20.15) was an independent predictor of respiratory failure (PaO2 /FiO(2) ratio<300).
ConclusionSoluble TM in BALF is an independent predictor of severe DLI. These findings underscore the importance of pulmonary endothelial injuries in the pathogenesis of severe DLI.
Soluble thrombomodulin in bronchoalveolar lavage is an independent predictor of severe drug-induced lung injury (DLI). Pulmonary endothelial injuries are an important aspect of pathogenesis in severe DLI.

DOI： 10.1111/resp.12965

Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis Reviewed International journal

Argyris Tzouvelekis, Jose D. Herazo-Maya, Martin Slade, Jen-Hwa Chu, Giuseppe Deiuliis, Changwan Ryu, Qin Li, Koji Sakamoto, Gabriel Ibarra, Hongyi Pan, Mridu Gulati, Danielle Antin-Ozerkis, Erica L. Herzog, Naftali Kaminski

RESPIROLOGY Vol. 22 ( 3 ) page： 486 - 493 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Background and objective: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and variable clinical course. Although matrix metalloproteinase-7 (MMP-7) is emerging as an important IPF biomarker, reproducibility across studies is unclear. We aimed to determine whether a previously reported prognostic threshold for MMP-7 was predictive of mortality in an independent cohort of IPF patients.
Methods: MMP-7 concentrations obtained from heparinized plasma samples were determined by ELISA in 97 patients with IPF and 41 healthy controls. The association of the previously published heparin plasma MMP-7 threshold of 12.1 ng/mL with all-cause mortality or transplant-free survival (TFS) was determined, either as an independent biomarker or as part of the modified personal clinical and molecular mortality index (m-PCMI).
Results: MMP-7 plasma concentrations were significantly higher in IPF patients compared to healthy controls (14.40 +/- 6.55 ng/mL vs 6.03 +/- 2.51 ng/mL, P < 0.001). The plasma MMP-7 threshold of 12.1 ng/mL was significantly associated with both all-cause mortality and TFS (unadjusted Cox proportional hazard ratio (HR) = 25.85 and 15.49, 95% CI: 10.91-61.23 and 5.41-44.34, respectively, P < 0.001). MMP-7 concentrations, split by 12.1 ng/mL, were significantly (P < 0.05) predictive of mortality and TFS after adjusting for age, gender, smoking and baseline pulmonary function parameters, in a multivariate Cox proportional hazards model. MMP-7 concentrations were negatively correlated with diffusing lung capacity of carbon monoxide (DLCO) (r = -0.21, P = 0.02), and positively with a mortality risk scoring system (GAP) that combines age, gender, forced vital capacity (FVC) and DLCO (r = 0.32, P = 0.001).
Conclusion: This study confirms that MMP-7 concentrations could be used to accurately predict outcomes across cohorts and centres, when similar collection protocols are applied.

DOI： 10.1111/resp.12920

Hemosiderin-laden macrophages are an independent factor correlated with pulmonary vascular resistance in idiopathic pulmonary fibrosis: a case control study Reviewed International journal

Jun Fukihara, Hiroyuki Taniguchi, Masahiko Ando, Yasuhiro Kondoh, Tomoki Kimura, Kensuke Kataoka, Taiki Furukawa, Takeshi Johkoh, Junya Fukuoka, Koji Sakamoto, Yoshinori Hasegawa

BMC PULMONARY MEDICINE Vol. 17 ( 1 ) page： 30 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Increases in hemosiderin-laden macrophages (HLM) are reported to be observed in idiopathic pulmonary fibrosis (IPF). According to a recent study, significant correlation between hemosiderin deposition in the lung tissue of IPF and pulmonary hypertension evaluated by echocardiography has been suspected. In this study, we aimed to evaluate whether HLM in bronchoalveolar lavage fluid (BALF) is a factor correlated with pulmonary hemodynamic parameters evaluated by right heart catheterization in patients with IPF.
Methods: Initial data from 103 consecutive patients with IPF who underwent surgical lung biopsy between November 2007 and March 2014 were retrospectively analyzed. The "HLM score" of BALF was established by dividing the number of Perls' Prussian blue stain positive macrophages by the total number of macrophages counted.
Results: BALF showed an elevated HLM score (38.2%). Right heart catheterization revealed mean pulmonary arterial pressure (mPAP) of 16.3 mmHg and pulmonary vascular resistance (PVR) of 1.55 Wood units. HLM score was positively correlated with mPAP (rho = 0.204; rho = 0.038) and PVR (rho = 0.349, rho < 0.001). In multivariate analysis, 6-min walk distance (standardized partial regression coefficient [beta], -0.391; p < 0.001), minimum oxygen saturation during 6-min walk distance (beta, -0.294; rho = 0.001) and HLM score (beta, 0.265; rho = 0.002) were independently correlated with PVR.
Conclusions: HLM score in BALF is an independent factor correlated with PVR in patients with IPF.

DOI： 10.1186/s12890-017-0376-8

SH2 Domain-Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis Reviewed International coauthorship International journal

Argyrios Tzouvelekis, Guoying Yu, Christian L. Lino Cardenas, Jose D. Herazo-Maya, Rong Wang, Tony Woolard, Yi Zhang, Koji Sakamoto, Hojin Lee, Jae-Sung Yi, Giuseppe Deluliis, Nikolaos Xylourgidis, Farida Ahangari, Patty J. Lee, Vassilis Aidinis, Erica L. Herzog, Robert Homer, Anton M. Bennett, Naftali Kaminski

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Vol. 195 ( 4 ) page： 500 - 514 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER THORACIC SOC

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with dismal prognosis and no cure. The potential role of the ubiquitously expressed SH2 domain-containing tyrosine phosphatase-2 (SHP2) as a therapeutic target has not been studied in IPF.
Objectives: To determine the expression, mechanistic role, and potential therapeutic usefulness of SHP2 in pulmonary fibrosis.
Methods: The effects of SHP2 overexpression and inhibition on fibroblast response to profibrotic stimuli were analyzed in vitro in primary human and mouse lung fibroblasts. In vivo therapeutic effects were assessed in the bleomycin model of lung fibrosis by SHP2-lentiviral administration and transgenic mice carrying a constitutively active SHP2 mutation.
Measurements and Main Results: SHP2 was down-regulated in lungs and lung fibroblasts obtained from patients with IPF. Immunolocalization studies revealed that SHP2 was absent within fibroblastic foci. Loss of SHP2 expression or activity was sufficient to induce fibroblast-to-myofibroblast differentiation in primary human lung fibroblasts. Overexpression of constitutively active SHP2 reduced the responsiveness offibroblasts to profibrotic stimuli, including significant reductions in cell survival and myofibroblast differentiation. SHP2 effects were mediated through deactivation of fibrosis-relevant tyrosine kinase and serine/threonine kinase signaling pathways. Mice carrying the Noonan syndrome-associated gain-of-function SHP2 mutation (SHP2(D61G/+)) were resistant to bleomycin-induced pulmonary fibrosis. Restoration of SHP2 levels in vivo through lentiviral delivery blunted bleomycin-induced pulmonary fibrosis.
Conclusions: Our data suggest that SHP2 is an important regulator of fibroblast differentiation, and its loss as observed in IPF facilitates profibrotic phenotypic changes. Augmentation of SHP2 activity or expression should be investigated as a novel therapeutic strategy for IPF.

DOI： 10.1164/rccm.201602-0329OC

The St. George's Respiratory Questionnaire as a prognostic factor in IPF Reviewed International journal

Taiki Furukawa, Hiroyuki Taniguchi, Masahiko Ando, Yasuhiro Kondoh, Kensuke Kataoka, Osamu Nishiyama, Takeshi Johkoh, Junya Fukuoka, Koji Sakamoto, Yoshinori Hasegawa

RESPIRATORY RESEARCH Vol. 18 ( 1 ) page： 18 2017.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: It is unclear whether health related quality of life (HRQL) may have a predictive value for mortality in idiopathic pulmonary fibrosis (IPF). We investigated the relationship between HRQL assessed using the St. George's Respiratory Questionnaire (SGRQ) and survival time in patients with IPF, and tried to determine a clinical meaningful cut off value to predict poorer survival rates.
Methods: We retrospectively analyzed consecutive patients with IPF who underwent an initial evaluation from May 2007 to December 2012. The diagnosis of IPF was made according to the 2011 international consensus guidelines. We used Cox proportional hazard models to identify independent predictors for mortality rate in patients with IPF.
Results: We examined 182 eligible cases, average age was 66 years old, and 86% were male. Mean levels of percent predicted FVC, DLco, six-minute-walk test distance, and the SGRQ total score were around 80%, 58%, 580 m, and 34 points. On multivariate analysis, the SGRQ total score (hazard ratio [HR], 1.012; 95% confidence interval [CI] 1.001-1.023; P = .029) and percent predicted FVC (HR, 0.957; 95% CI 0.944-0.971, P < .001) were independent predictors for mortality rate. Moreover, a score higher than 30 points in the SGRQ total score showed higher mortality rate (HR, 2.047; 95% CI, 1.329-3.153; P = .001).
Conclusions: The SGRQ total score was one of independent prognostic factors in patients with IPF. Total scores higher than 30 points were associated with higher mortality rates.

DOI： 10.1186/s12931-017-0503-3

Impact of mild to moderate COPD on feasibility and prognosis in non-small cell lung cancer patients who received chemotherapy

Exercise hypoxaemia as a predictor of pulmonary hypertension in COPD patients without severe resting hypoxaemia. Reviewed

Nakahara Y, Taniguchi H, Kimura T, Kondoh Y, Arizono S, Nishimura K, Sakamoto K, Ito S, Ando M, Hasegawa Y

Respirology (Carlton, Vic.) Vol. 22 ( 1 ) page： 120-125 2017.1

Exogenous induction of unphosphorylated PTEN reduces TGFβ-induced extracellular matrix expressions in lung fibroblasts. Reviewed

Vol. 25 ( 1 ) page： 86-97 2017.1

Depression Is Significantly Associated with the Health Status in Patients with Idiopathic Pulmonary Fibrosis. Reviewed

Matsuda T, Taniguchi H, Ando M, Kondoh Y, Kimura T, Kataoka K, Nishimura K, Nishiyama O, Sakamoto K, Hasegawa Y

Internal medicine (Tokyo, Japan) Vol. 56 ( 13 ) page： 1637-1644 2017

Norihito Omote, Naozumi Hashimoto, Masahiro Morise, Koji Sakamoto, Shinichi Miyazaki, Akira Ando, Yoshio Nakahara, Yoshinori Hasegawa

INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Vol. 12 page： 3541 - 3547 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：DOVE MEDICAL PRESS LTD

Background: Non-small cell lung cancer (NSCLC) is the predominant cause of death in patients with COPD, and the severity of COPD in NSCLC patients is classified mainly as mild to moderate. Most advanced NSCLC patients with mild to moderate COPD are treated with chemotherapy; however, the feasibility for and prognosis after chemotherapy of these patients are not well understood. The aim of this study was to elucidate the impact of mild to moderate COPD on the feasibility for and prognosis after chemotherapy in NSCLC patients.
Patients and methods: A retrospective review was performed on 268 NSCLC patients who received first-line chemotherapy from 2009 to 2014 in our institution. Finally, 85 evaluable patients were included in this study. The clinical characteristics, toxicity profile, objective response rate, and prognosis were analyzed and compared between patients with mild to moderate COPD and those without COPD (non-COPD).
Results: Forty-three patients were classified as COPD (27 cases mild and 16 cases moderate) and 42 patients as non-COPD. The COPD group were older and had fewer never-smokers than the non-COPD group. The objective response rate did not differ between groups (p=0.14). There was no significant difference in overall survival between COPD and non-COPD groups (15.0 and 17.0 months, log-rank test p= 0.57). In the multivariate Cox's proportional hazard model, the adjusted hazard ratio (HRadj) was statistically significant for male sex (HRadj =5.382, 95% CI: 1.496-19.359; p=0.010), pathological diagnosis of adenocarcinoma (HRadj =0.460, 95% CI: 0.223-0.948; p=0.035), and epithelial growth factor receptor negative mutation (HRadj =6.040, 95% CI: 1.158-31.497; p=0.033), but not for the presence of COPD (HRadj =0.661, 95% CI: 0.330-1.325; p=0.24). Toxicity profile in COPD group was favorable, as in the non-COPD group.
Conclusion: Mild to moderate COPD did not have a significant deleterious impact on toxicity and prognosis in NSCLC patients.

DOI： 10.2147/COPD.S149456