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Fibrosing interstitial lung diseases (FILDs), e.g., due to idiopathic pulmonary fibrosis (IPF), are chronic progressive diseases with a poor prognosis. The management of these diseases is challenging and focuses mainly on the suppression of progression with anti-fibrotic drugs. Therefore, novel FILD treatments are needed. In recent years, cell-based therapy with various stem cells has been investigated for FILD, and the use of mesenchymal stem cells (MSCs) has been widely reported and clinical studies are also ongoing. Induced pluripotent stem cells (iPSCs) have also been reported to have an anti-fibrotic effect in FILD; however, these have not been as well studied as MSCs in terms of the mechanisms and side effects. While MSCs show a potent anti-fibrotic effect, the possibility of quality differences between donors and a stable supply in the case of donor shortage or reduced proliferative capacity after cell passaging needs to be considered. The application of iPSC-derived cells has the potential to overcome these problems and may lead to consistent quality of the cell product and stable product supply. This review provides an overview of iPSCs and FILD, followed by the current status of cell-based therapy for FILD, and then discusses the possibilities and perspectives of FILD therapy with iPSC-derived cells.

Pulmonary fibrosis is a life-threatening disease that has been attributed to several causes. Specifically, vascular injury is thought to be involved in the pathogenesis of fibrosis. The effects of the antifibrotic drug pirfenidone on angiogenesis have not been fully elucidated. This study aimed to investigate the effects of pirfenidone in human lung fibroblast–endothelial cell co-culture network formation and to analyze the underlying molecular mechanisms. Human lung fibroblasts were co-cultured with human umbilical vein endothelial cells to establish a co-culture network cell sheet. The influence of pirfenidone was evaluated for protective effect on the endothelial network in cell sheets stimulated with transforming growth factor β (TGF-β). Results indicated that TGF-β disrupted the network formation. Pirfenidone and Y27632 (Rho-associated coiled-coil containing protein kinase [Rho-kinase or ROCK] inhibitor) protected against the TGF-β–induced endothelial network disruption. TGF-β activated Rho-kinase signaling in cells composing the co-culture cell sheet, whereas pirfenidone and Y27632 inhibited these effects. In conclusion, TGF-β–induced Rho-kinase activation and disrupted endothelial network formation. Pirfenidone suppressed TGF-β–induced Rho-kinase activity in cell sheets, thereby enabling vascular endothelial cells networks to be preserved in the cell sheets. These findings suggest that pirfenidone has potential vascular network–preserving effect via inhibiting Rho-kinase activity in vascular injury, which is a precursor to pulmonary fibrosis.

Objective: We aimed to determine the relationship between vaccine-related adverse effects and antibody (Ab) titers from 3 to 6 months after the second dose of the BNT162b2 coronavirus disease 2019 (COVID-19) mRNA vaccine (Pfizer/BioNTech) in Japan. Methods: We enrolled 378 healthcare workers (255 women and 123 men) whose Ab titers were analyzed 3 and 6 months after the second dose in our previous study and whose characteristics and adverse effects were collected previously by using a structured self-report questionnaire. Results: The workers’ median age was 44 years. Although injection-site symptoms occurred with almost equal frequency between the first and second doses, systemic adverse effects, such as general fatigue and fever, were significantly more frequent after the second dose than after the first dose. Multivariate analysis showed that fever was significantly correlated with female participants for the second dose (odds ratio (OR), 2.139; 95% confidence interval (95% CI), 1.185–3.859), older age for the first dose (OR, 0.962; 95% CI, 0.931–0.994) and second dose (OR, 0.957; 95% CI, 0.936–0.979), and dyslipidemia for the first dose (OR, 8.750; 95% CI, 1.814–42.20). Age-adjusted Ab titers at 3 months after vaccination were 23.7% and 23.4% higher in patients with a fever than in those without a fever after the first and second dose, respectively. In addition, age-adjusted Ab titers at 3 and 6 months after the second dose were, respectively, 21.7% and 19.3% higher in the group in which an anti-inflammatory agent was used than in the group without the use of an anti-inflammatory agent. Conclusion: Participants with systemic adverse effects tend to have higher Ab titers from 3 to 6 months after the second dose of the BNT162b2 vaccine. Our results may encourage vaccination, even among people with vaccine hesitancy related to relatively common systemic adverse effects.

Objective: We aimed to determine antibody titers at six months and their percentage change from three to six months after the second dose of the BNT162b2 coronavirus disease 2019 (COVID-19) mRNA vaccine (Pfizer/BioNTech) and to explore clinical variables associated with titers in Japan. Methods: We enrolled 365 healthcare workers (250 women, 115 men) whose three-month antibody titers were analyzed in our previous study and whose blood samples were collected 183 ± 15 days after the second dose. Participant characteristics, collected previously, were used. The relationships of these factors with antibody titers at six months and percentage changes in antibody titers from three to six months were analyzed. Results: Median age was 44 years. Median antibody titer at six months was 539 U/mL. Older participants had significantly lower antibody titers (20s, 752 U/mL; 60s–70s, 365 U/mL). In age-adjusted analysis, smoking was the only factor associated with lower antibody titers. Median percentage change in antibody titers from three to six months was −29.4%. The only factor significantly associated with the percentage change in Ab titers was not age or smoking, but sex (women, −31.6%; men, −25.1%). Conclusion: The most important factors associated with lower antibody titers at six months were age and smoking, as at three months, probably reflecting their effect on peak antibody titers. However, the only factor significantly associated with the attenuation in Ab titers from three to six months was sex, which reduced the sex difference seen during the first three months. Antibody titers may be affected by different factors at different time points.

Objective: We aimed to determine antibody (Ab) titres 3 months after the second dose of the BNT162b2 coronavirus disease-2019 (COVID-19) vaccine and to explore clinical variables predicting these titres in Japan. Methods: We enrolled 378 healthcare workers (255 women, 123 men) whose blood samples were collected 91 ± 15 days after the second of two inoculations of the BNT162b2 COVID-19 mRNA vaccine (Pfizer/BioNTech) given 3 weeks apart. Medical histories and demographic characteristics were recorded using a structured self-reported questionnaire. The relationships between Ab titres and these factors were analysed. Results: Median age (interquartile range (IQR)) of the participants was 44 (32–54) years. Median Ab titre (IQR) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen was 764 (423–1140) U/mL. Older participants had significantly lower Ab titres; median (IQR) Ab titres were 942 (675–1390) and 1095 (741–1613) U/mL in men and women in their 20s, respectively, but 490 (297–571) and 519 (285–761) U/mL in men and women in their 60–70s, respectively. In the age-adjusted analysis, the only risk factors for lower Ab titres were male sex and smoking. However, the sex difference may have arisen from the sex difference in smoking rate. Moreover, Ab titres were significantly lower in current smokers than in ex-smokers. Conclusions: The most important factors associated with low Ab titres were age and smoking habit. In particular, current smoking status caused lower Ab titres, and smoking cessation before vaccination may improve the individual efficacy of the BNT162b2 vaccine.