Mitsuo Otsuka

Following publication of the original article [1], the authors have flagged that there is an error in Fig. 3.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with poor prognosis. Pirfenidone and nintedanib are anti-fibrotic drugs used for patients with IPF. These drugs reduce the rate of decline in forced vital capacity (FVC). Serum surfactant protein (SP)-A, SP-D, and Krebs von den Lungen-6 (KL-6) are monitoring and prognostic biomarkers in patients with IPF; however, their relationship with the therapeutic outcomes of anti-fibrotic drugs has not been investigated. We aim to clarify whether serum SP-A, SP-D, and KL-6 reflect therapeutic outcomes of pirfenidone and nintedanib administration in patients with IPF. Methods: We retrospectively investigated patients with IPF who were initiated on pirfenidone or nintedanib administration between January 2014 and June 2018 at our hospital. Changes in clinical parameters and serum SP-A, SP-D, and KL-6 levels were evaluated. Patients with ≥10% decline in FVC or ≥ 15% decline in diffusing capacity of the lung for carbon monoxide (DLco) from baseline to 6 months were classified as progression group, while the other patients were classified as stable group. Results: Forty-nine patients were included (pirfenidone, 23; nintedanib, 26). Stable group comprised 32 patients, while progression group comprised 17 patients. In the stable group, changes in SP-A and KL-6 from baseline to 3 and 6 months significantly decreased compared with the progression group (SP-A: 3 months − 6.0% vs 16.7%, 6 months − 10.2% vs 20.2%, KL-6: 3 months − 9.2% vs 6.7%, 6 months − 15.0% vs 12.1%, p < 0.05). Changes in SP-A and SP-D levels showed significant negative correlations with the change in %FVC (r = − 0.46 and r = − 0.39, p < 0.01, respectively) and %DLco (r = − 0.67 and r = − 0.54, p < 0.01, respectively). Similar results were also seen in subgroup analysis for both pirfenidone and nintedanib groups. On logistic regression analysis, decrease in SP-A from baseline to 3 months and 6 months was found to predict the outcomes at 6 months (odds ratios: 0.89 and 0.88, respectively). Conclusions: Changes in serum SP-A reflected the outcomes of anti-fibrotic drug therapy. Serum SP-A has a potential as a biomarker of therapeutic outcomes of anti-fibrotic drugs.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by extracellular matrix deposition in lung interstitium. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel activated by physical stimuli and arachidonic acid metabolites. In a recent study, TRPV4-deficient mice did not develop bleomycin-induced lung fibrosis. Pirfenidone is an antifibrotic agent used to treat patients with IPF, although its underlying antifibrotic mechanism is poorly understood. Aims and Objectives: To investigate the effect of TRPV4 blockade by pirfenidone and the role of TRPV4 in lung fibrosis. Methods: We measured the agonist-induced Ca²⁺ influx of TRPV4 to determine whether its channel activation was inhibited by pirfenidone. A TRPV4 antagonist and pirfenidone were also evaluated in a mouse model of bleomycin-induced lung fibrosis. Arachidonic acid metabolites were determined using a targeted lipidomics approach in fibrotic lung from mice and bronchoalveolar lavage fluid (BALF) from patients with IPF prior to pirfenidone treatment. Results: TRPV4-mediated Ca²⁺ influx was inhibited by pirfenidone. The TRPV4 antagonist and pirfenidone significantly improved lung fibrosis. Arachidonic acid metabolite levels increased in fibrotic lung and were reduced by pirfenidone. Change in forced vital capacity of patients with IPF treated with pirfenidone significantly correlated with arachidonic acid metabolite levels in BALF (n = 8, r = 0.79, p = 0.02). Conclusions: The antifibrotic action of pirfenidone appears to be partly mediated by TRPV4. Levels of arachidonic acid metabolites in BALF may predict the antifibrotic efficacy of pirfenidone.

Objective. Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare disease characterized by predominant upper lobe pulmonary fibrosis of unknown etiology. However, the prognosis of IPPFE has not been discussed. We investigated the clinical characteristics and prognostic factors of IPPFE and idiopathic pulmonary fibrosis (IPF). Methods. We performed a retrospective cohort study on 375 consecutive idiopathic interstitial pneumonia patients between April 2004 and December 2014. Among them, we diagnosed IPPFE and IPF patients using high-resolution computed tomography radiological criteria. Results. Twenty-nine IPPFE patients (9 males, 20 females) and 67 IPF patients (54 males, 13 females) were enrolled. IPPFE patients were significantly more likely to be females and nonsmokers and had lower body mass index, lower values of predicted percentage of forced vital capacity (%FVC), and a higher residual volume-to-total lung capacity ratio than IPF patients. Survival analysis revealed that they had significantly poorer prognosis than IPF patients in GAP (gender, age, and physiology) stages II + III. %FVC and GAP index independently predict mortality in patients with IPPFE. Conclusions. Patients with IPPFE showed poorer prognosis in the advanced stage than patients with IPF. %FVC and GAP index are independent predictors of survival in patients with IPPFE.

Background: Idiopathic pulmonary fibrosis (IPF) is a well-known life threatening disease, which the progressive lung fibrosis leads to restrictive ventilatory impairment and diffusion failure. While IPF seems to be uncorrelated with infectious subjects, several papers indicated that microbiome composition correlates with progression of IPF. However, the roles of microbiome against respiratory functions and clinical biomarkers in IPF remain unknown. In this study, we examined the relationship between microbial environment in the lung and clinical findings. Methods: Subjects included in this analysis were IPF patients who visited Sapporo Medical University Hospital with approval of the hospital ethics board retrospectively. 16s rRNA were purified from bronchial alveolar lavage fluids obtained at the time of diagnosis and next generation sequencing techniques were used to characterize the bacterial communities. These data were compared with the clinical data of each patients. Results: As a result of sequencing, the most dominant lung phyla were Firmicutes, Proteobacteria and Bacteroidetes. The bacterial diversity was significantly lower in the unstable group, which the decline in forced vital capacity (FVC) was observed during a year. FVC are inversely proportional to the relative abundance of Firmicutes. Also, Streptococcuceae, the largest family OTU in a member of the Firmicutes, was significantly associated with FVC, 6-minute walk distance and serum KL-6. Conclusions: Our study revealed there were some relationships between specific taxa in BALF and clinical findings. Further study of lung microbiome may provide further insights into its possible contribution to IPF pathogenesis and new biomarker.

Surfactant proteins SP-A and SP-D are useful biomarkers in diagnosis, monitoring, and prognosis of idiopathic pulmonary fibrosis (IPF). Despite their high structural homology, their serum concentrations often vary in IPF patients. This retrospective study aimed to investigate distinct compartmentalization of SP-A and SP-D in the vasculature and lungs by bronchoalveolar lavage fluid (BALF)/serum analysis, hydrophilicity and immunohistochemistry. We included 36 IPF patients, 18 sarcoidosis (SAR) patients and 20 healthy subjects. Low-speed centrifugal supernatants of BALF (Sup-1) were obtained from each subject. Sera were also collected from each patient. Furthermore, we separated Sup-1 of IPF patients into hydrophilic supernatant (Sup-2) and hydrophobic precipitate (Ppt) by high-speed centrifugation. We measured SP-A and SP-D levels of each sample with the sandwich ELISA technique. We analyzed the change of the BALF/serum level ratios of the two proteins in IPF patients and their hydrophilicity in BALF. The distribution in the IPF lungs was also examined by immunohistochemical staining. In BALF, SP-A levels were comparable between the groups; however, SP-D levels were significantly lower in IPF patients than in others. Although IPF reduced the BALF/serum level ratios of the two proteins, the change in concentration of SP-D was more evident than SP-A. This suggests a higher disease impact for SP-D. Regarding hydrophilicity, although more than half of the SP-D remained in hydrophilic fractions (Sup-2), almost all of the SP-A sedimented in the Ppt with phospholipids. Hydrophilicity suggests that SP-D migrates into the blood more easily than SP-A in IPF lungs. Immunohistochemistry revealed that SP-A was confined to thick mucus-filling alveolar space, whereas SP-D was often intravascular. This data also suggests that SP-D easily leaks into the bloodstream, whereas SP-A remains bound to surfactant lipids in the alveolar space. The current study investigated distinct compartmentalization of SP-A and SP-D in the vasculature and lungs. Our results suggest that serum levels of SP-D could reflect pathological changes of the IPF lungs more incisively than those of SP-A.