Transforming Growth Factor-ß1 Regulates Peroxisomal Genes/Proteins via Smad Signaling in Idiopathic Pulmonary Fibrosis Fibroblasts and Transgenic Mouse Models.

Idiopathic pulmonary fibrosis (IPF) is a chronic human disease with persistent destruction of lung parenchyma. Transforming growth factor-ß1 (TGF-ß1) signaling plays a pivotal role in the initiation and pathogenesis of IPF. As shown herein, TGF-ß1 signaling down-regulated not only peroxisome biogenesis but also the metabolism of these organelles in human IPF fibroblasts. In vitro cell culture observations in human fibroblasts and human lung tissue indicated that peroxisomal biogenesis and metabolic proteins were significantly down-regulated in the lung of 1-month-old transgenic mice expressing a constitutively active TGF-ß type I receptor kinase (ALK5). The peroxisome biogenesis protein peroxisomal membrane protein Pex13p (PEX13p) as well as the peroxisomal lipid metabolic enzyme peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) and antioxidative enzyme catalase were highly up-regulated in TGF-ß type II receptor and Smad3 knockout mice. This study reports a novel mechanism of peroxisome biogenesis and metabolic regulation via TGF-ß1-Smad signaling: interaction of the Smad3 transcription factor with the PEX13 gene in chromatin immunoprecipitation-on-chip assay as well as in a bleomycin-induced pulmonary fibrosis model applied to TGF-ß type II receptor knockout mice. Taken together, data from this study suggest that TGF-ß1 participates in regulation of peroxisomal biogenesis and metabolism via Smad-dependent signaling, opening up novel strategies for the development of therapeutic approaches to inhibit progression of pulmonary fibrosis patients with IPF.

Role of airway epithelial cell miRNAs in asthma.

The airway epithelial cells and overlying layer of mucus are the first point of contact for particles entering the lung. The severity of environmental contributions to pulmonary disease initiation, progression, and exacerbation is largely determined by engagement with the airway epithelium. Despite the cellular cross-talk and cargo exchange in the microenvironment, epithelial cells produce miRNAs associated with the regulation of airway features in asthma. In line with this, there is evidence indicating miRNA alterations related to their multifunctional regulation of asthma features in the conducting airways. In this review, we discuss the cellular components and functions of the airway epithelium in asthma, miRNAs derived from epithelial cells in disease pathogenesis, and the cellular exchange of miRNA-bearing cargo in the airways.

Oral application of vancomycin alters murine lung microbiome and pulmonary immune responses.

Early life exposures to antibiotics negatively impact respiratory health and are associated with an increased risk of childhood asthma. It is explained that the lung is inclined to develop chronic inflammatory phenotypes due to early antibiotic alteration in the gut microbiome. We investigated whether a gut-targeted antibiotic has an impact on the lung microbiome and on pulmonary immunity. Fourteen-day old C57BL/6 mice were administered with vancomycin via oral gavage for 3 days (1 time/day). Control groups were treated with clarithromycin and phosphate-buffered saline (PBS), respectively. Five days after treatment, the cecum and lung microbiome, and pulmonary immune response were analyzed. Vancomycin treatment decreased the relative abundance of the genera Clostridium XIVa and Alistipes and the family Lachnospiraceae in the cecum. Furthermore, the relative abundance of the family Parabacteroidetes and the genus Lactobacillus were increased, whereas the abundance of the phylum Firmicutes was decreased. In the lung, vancomycin treatment reduced bacteria belonging to Clostridium XIVa and the family Lachnospiraceae as compared to those in the clarithromycin treated group. Lung cells from the vancomycin-treated mice released higher levels of interleukin (IL)-4 and IL-13 compared to those from the PBS group, and increased levels of IL-6, IFN-γ, and TNFα compared to lung cells from the clarithromycin and PBS treated mice. Our pilot study suggests that alteration in the gut microbiome could affect bacterial composition and immunity of the lung hence proposes a gut-lung microbiome axis in early life.

Exposures during the prepuberty period and future offspring's health: evidence from human cohort studies†.

Emerging evidence suggests that exposures in prepuberty, particularly in fathers-to-be, may impact the phenotype of future offspring. Analyses of the RHINESSA cohort find that offspring of father's exposed to tobacco smoking or overweight that started in prepuberty demonstrate poorer respiratory health in terms of more asthma and lower lung function. A role of prepuberty onset smoking for offspring fat mass is suggested in the RHINESSA and ALSPAC cohorts, and historic studies suggest that ancestral nutrition during prepuberty plays a role for grand-offspring's health and morbidity. Support for causal relationships between ancestral exposures and (grand-)offspring's health in humans has been enhanced by advancements in statistical analyses that optimize the gain while accounting for the many complexities and deficiencies in human multigeneration data. The biological mechanisms underlying such observations have been explored in experimental models. A role of sperm small RNA in the transmission of paternal exposures to offspring phenotypes has been established, and chemical exposures and overweight have been shown to influence epigenetic programming in germ cells. For example, exposure of adolescent male mice to smoking led to differences in offspring weight and alterations in small RNAs in the spermatozoa of the exposed fathers. It is plausible that male prepuberty may be a time window of particular susceptibility, given the extensive epigenetic reprogramming taking place in the spermatocyte precursors at this age. In conclusion, epidemiological studies in humans, mechanistic research, and biological plausibility, all support the notion that exposures in the prepuberty of males may influence the phenotype of future offspring.

Precision medicine reaching out to the patients in allergology - a German-Japanese workshop report.

An expert workshop in collaboration of the German Society of Allergy and Clinical Immunology (DGAKI) and the Japanese Society of Allergy (JSA) provided a platform for key opinion leaders of both countries aimed to join expertise and to highlight current developments and achievements in allergy research. Key domains of the meeting included the following seven main sections and related subchapters: 1) basic immunology, 2) bronchial asthma, 3) prevention of allergic diseases, 4) food allergy and anaphylaxis, 5) atopic dermatitis, 6) venom allergy, and 7) upper airway diseases. This report provides a summary of panel discussions of all seven domains and highlights unmet needs and project possibilities of enhanced collaborations of scientific projects.

Preconceptional smoking alters spermatozoal miRNAs of murine fathers and affects offspring's body weight.

BACKGROUND: Active smoking has been reported among 7% of teenagers worldwide, with ages ranging from 13 to 15 years. An epidemiological study suggested that preconceptional paternal smoking is associated with adolescent obesity in boys. We developed a murine adolescent smoking model before conception to investigate the paternal molecular causes of changes in offspring's phenotype. METHOD: Male and female C57BL/6J mice were exposed to increasing doses of mainstream cigarette smoke (CS) from onset of puberty for 6 weeks and mated with room air (RA) controls. RESULTS: Thirteen miRNAs were upregulated and 32 downregulated in the spermatozoa of CS-exposed fathers, while there were no significant differences in the count and morphological integrity of spermatozoa, as well as the proliferation of spermatogonia between CS- and RA-exposed fathers. Offspring from preconceptional CS-exposed mothers had lower body weights (p = 0.007). Moreover, data from offspring from CS-exposed fathers suggested a potential increase in body weight (p = 0.062). CONCLUSION: We showed that preconceptional paternal CS exposure regulates spermatozoal miRNAs, and possibly influences the body weight of F1 progeny in early life. The regulated miRNAs may modulate transmittable epigenetic changes to offspring, thus influence the development of respiratory- and metabolic-related diseases such as obesity, a mechanism that warrants further studies for elaborate explanations.

miRNAs in Lung Development and Diseases.

The development of the lung involves a diverse group of molecules that regulate cellular processes, organ formation, and maturation. The various stages of lung development are marked by accumulation of small RNAs that promote or repress underlying mechanisms, depending on the physiological environment in utero and postnatally. To some extent, the pathogenesis of various lung diseases is regulated by small RNAs. In this review, we discussed miRNAs regulation of lung development and diseases, that is, COPD, asthma, pulmonary fibrosis, and pulmonary arterial hypertension, and also highlighted possible connotations for human lung health.

Hippo signaling promotes lung epithelial lineage commitment by curbing Fgf10 and ß-catenin signaling.

Organ growth and tissue homeostasis rely on the proliferation and differentiation of progenitor cell populations. In the developing lung, localized Fgf10 expression maintains distal Sox9-expressing epithelial progenitors and promotes basal cell differentiation in the cartilaginous airways. Mesenchymal Fgf10 expression is induced by Wnt signaling but inhibited by Shh signaling, and epithelial Fgf10 signaling activates ß-catenin signaling. The Hippo pathway is a well-conserved signaling cascade that regulates organ size and stem/progenitor cell behavior. Here, we show that Hippo signaling promotes lineage commitment of lung epithelial progenitors by curbing Fgf10 and ß-catenin signaling. Our findings show that both inactivation of the Hippo pathway (nuclear Yap) or ablation of Yap result in increased ß-catenin and Fgf10 signaling, suggesting a cytoplasmic role for Yap in epithelial lineage commitment. We further demonstrate redundant and non-redundant functions for the two nuclear effectors of the Hippo pathway, Yap and Taz, during lung development.

Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-ß signaling.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces liver fibrosis. However, altered peroxisome functions in IPF pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and IPF patients, we found that IPF lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism (e.g., PEX13p and acyl-CoA oxidase 1). Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta (TGF-ß) receptor II knockout mice indicating a role for TGF-ß signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of IPF fibroblasts with the profibrotic factors TGF-ß1 or tumor necrosis factor alpha (TNF-α) was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced fibrosis were further studied. Direct down-regulation of PEX13 by RNAi induced the activation of Smad-dependent TGF-ß signaling accompanied by increased ROS production and resulted in the release of cytokines (e.g., IL-6, TGF-ß) and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-α activators, led to peroxisome proliferation and reduced the TGF-ß-induced myofibroblast differentiation and collagen protein in IPF cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of IPF and fibrosis progression, possibly by exacerbating pulmonary inflammation and intensifying the fibrotic response in the patients.