Preterm birth poses a global challenge with a continuously increasing disease burden during the last decades. Advances in understanding the etiopathogenesis did not lead to a reduction of prematurely ...born infants so far. A balanced development of the host microbiome in early life is key for the maturation of the immune system and many other physiological functions. With the tremendous progress in new diagnostic possibilities, the contribution of microbiota changes to preterm birth and the acute and long-term sequelae of prematurity have come into the research focus. This review summarizes the latest advances in the understanding of microbiomes in the amniotic cavity and the female lower genital tract and how changes in microbiota structures contribute to preterm delivery. The exhibition of these highly vulnerable infants to the hostile environment in the neonatal intensive care unit necessarily entails the rapid colonization with a nonbalanced microbiome in a situation where the organism is still very prone and at an early stage of development. The global research efforts to decipher pathologic changes will pave the way to new pre- and postnatal therapeutic concepts.
The fetal immune system is characterized by a Th2 bias but it is unclear how the Th2 predominance is established. Natural killer T (NKT) cells are a rare subset of T cells with immune regulatory ...functions and are already activated in utero. To test the hypothesis that NKT cells are part of the regulatory network that sets the fetal Th2 predominance, percentages of Vα24(+)Vβ11(+) NKT cells expressing Th1/Th2-related chemokine receptors (CKR) were assessed in cord blood. Furthermore, IL-4 and IFN-γ secreting NKT cells were quantified within the single CKR(+) subsets.
Cord blood NKT cells expressed the Th2-related CCR4 and CCR8 at significantly higher frequencies compared to peripheral blood NKT cells from adults, while CXCR3(+) and CCR5(+) cord blood NKT cells (Th1-related) were present at lower percentages. Within CD4(neg)CD8(neg) (DN) NKT cells, the frequency of IL-4 producing NKT cells was significantly higher in cord blood, while frequencies of IFN-γ secreting DN NKT cells tended to be lower. A further subanalysis showed that the higher percentage of IL-4 secreting DN NKT cells was restricted to CCR3(+), CCR4(+), CCR5(+), CCR6(+), CCR7(+), CCR8(+) and CXCR4(+) DN subsets in cord blood. This resulted in significantly decreased IFN-γ /IL-4 ratios of CCR3(+), CCR6(+) and CCR8(+) cord blood DN NKT cells. Sequencing of VA24AJ18 T cell receptor (TCR) transcripts in sorted cord blood Vα24Vβ11 cells confirmed the invariant TCR alpha-chain ruling out the possibility that these cells represent an unusual subset of conventional T cells.
Despite the heterogeneity of cord blood NKT cells, we observed a clear Th2-bias at the phenotypic and functional level which was mainly found in the DN subset. Therefore, we speculate that NKT cells are important for the initiation and control of the fetal Th2 environment which is needed to maintain tolerance towards self-antigens as well as non-inherited maternal antigens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intrauterine and early life has been accepted as important susceptibility windows for environmental exposure and disease later in life. Emerging evidence suggests that exposure before conception may ...also influence health in future generations. There has been little research on human data to support this until now. This review gives evidence from epigenetic as well as immunologic research, and from animal as well as human models, supporting the hypothesis that there may be important susceptibility windows before conception in relation to exposure such as obesity, diet, smoking and infections. It is likely that we can identify vulnerability windows in men and women in which interventions may have an impact on several generations in addition to individual health. Establishing vulnerability windows affecting health over future generations, and not only in the now or the near future of the individual, may provide tremendous opportunities for health policy and practice.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Interstitial lung diseases (ILD) are chronic inflammatory disorders leading to pulmonary fibrosis. Monocyte chemotactic protein 1 (MCP-1) promotes collagen synthesis and deletion of the MCP-1 ...receptor CCR2 protects from pulmonary fibrosis in ILD mouse models. We hypothesized that pulmonary MCP-1 and CCR2+ T cells accumulate in pediatric ILD and are related to disease severity.
Bronchoalveolar lavage fluid was obtained from 25 children with ILD and 10 healthy children. Levels of pulmonary MCP-1 and Th1/Th2-associated cytokines were quantified at the protein and the mRNA levels. Pulmonary CCR2+, CCR4+, CCR3+, CCR5+ and CXCR3+ T cells were quantified by flow-cytometry.
CCR2+ T cells and MCP-1 levels were significantly elevated in children with ILD and correlated with forced vital capacity, total lung capacity and ILD disease severity scores. Children with lung fibrosis had significantly higher MCP-1 levels and CCR2+ T cells in bronchoalveolar lavage fluid compared to non-fibrotic children.
The results indicate that pulmonary CCR2+ T cells and MCP-1 contribute to the pathogenesis of pediatric ILD and might provide a novel target for therapeutic strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The lower respiratory tract has been previously considered sterile in a healthy state, but advances in culture-independent techniques for microbial identification and characterization have revealed ...that the lung harbors a diverse microbiome. Although research on the lung microbiome is increasing and important questions were already addressed, longitudinal studies aiming to describe developmental stages of the microbial communities from the early neonatal period to adulthood are lacking. Thus, little is known about the earlylife development of the lung microbiome and the impact of external factors during these stages. In this study, we applied a barcoding approach based on high-throughput sequencing of 16S ribosomal RNA gene amplicon libraries to determine age-dependent differences in the bacterial fraction of the murine lung microbiome and to assess potential influences of differing “environmental microbiomes” (simulated by the application of used litter material to the cages). We could clearly show that the diversity of the bacterial community harbored in the murine lung increases with age. Interestingly, bacteria belonging to the genera Delftia and Rhodococcus formed an age-independent core microbiome. The addition of the used litter material influenced the lung microbiota of young mice but did not significantly alter the community composition of adult animals. Our findings elucidate the dynamic nature of the early-life lung microbiota and its stabilization with age. Further, this study indicates that even slight environmental changes modulate the bacterial community composition of the lung microbiome in early life, whereas the lung microbes of adults demonstrate higher resilience towards environmental variations.
Whereas it is generally accepted that maternal environment plays a key role in child health, emerging evidence suggests that paternal environment before conception also impacts child health. We aimed ...to investigate the association between children's asthma risk and parental smoking and welding exposures prior to conception.
In a longitudinal, multi-country study, parents of 24 168 offspring aged 2-51 years provided information on their life-course smoking habits, occupational exposure to welding and metal fumes, and offspring's asthma before/after age 10 years and hay fever. Logistic regressions investigated the relevant associations controlled for age, study centre, parental characteristics (age, asthma, education) and clustering by family.
Non-allergic early-onset asthma (asthma without hay fever, present in 5.8%) was more common in the offspring with fathers who smoked before conception {odds ratio OR = 1.68 95% confidence interval (CI) = 1.18-2.41}, whereas mothers' smoking before conception did not predict offspring asthma. The risk was highest if father started smoking before age 15 years 3.24 (1.67-6.27), even if he stopped more than 5 years before conception 2.68 (1.17-6.13). Fathers' pre-conception welding was independently associated with non-allergic asthma in his offspring 1.80 (1.29-2.50). There was no effect if the father started welding or smoking after birth. The associations were consistent across countries.
Environmental exposures in young men appear to influence the respiratory health of their offspring born many years later. Influences during susceptible stages of spermatocyte development might be important and needs further investigation in humans. We hypothesize that protecting young men from harmful exposures may lead to improved respiratory health in future generations.
Knowing the molecular makeup of an organ system is required for its in-depth understanding. We analyzed the molecular repertoire of the adult tracheal system of the fruit fly Drosophila melanogaster ...using transcriptome studies to advance our knowledge of the adult insect tracheal system. Comparing this to the larval tracheal system revealed several major differences that likely influence organ function. During the transition from larval to adult tracheal system, a shift in the expression of genes responsible for the formation of cuticular structure occurs. This change in transcript composition manifests in the physical properties of cuticular structures of the adult trachea. Enhanced tonic activation of the immune system is observed in the adult trachea, which encompasses the increased expression of antimicrobial peptides. In addition, modulatory processes are conspicuous, in this case mainly by the increased expression of G protein-coupled receptors in the adult trachea. Finally, all components of a peripheral circadian clock are present in the adult tracheal system, which is not the case in the larval tracheal system. Comparative analysis of driver lines targeting the adult tracheal system revealed that even the canonical tracheal driver line breathless (btl)-Gal4 is not able to target all parts of the adult tracheal system. Here, we have uncovered a specific transcriptome pattern of the adult tracheal system and provide this dataset as a basis for further analyses of the adult insect tracheal system.
Early life environmental influences such as exposure to cigarette smoke (CS) can disturb molecular processes of lung development and thereby increase the risk for later development of chronic ...respiratory diseases. Among the latter, asthma and chronic obstructive pulmonary disease (COPD) are the most common. The airway epithelium plays a key role in their disease pathophysiology but how CS exposure in early life influences airway developmental pathways and epithelial stress responses or survival is poorly understood.
Using Drosophila melanogaster larvae as a model for early life, we demonstrate that CS enters the entire larval airway system, where it activates cyp18a1 which is homologues to human CYP1A1 to metabolize CS-derived polycyclic aromatic hydrocarbons and further induces heat shock protein 70. RNASeq studies of isolated airways showed that CS dysregulates pathways involved in oxidative stress response, innate immune response, xenobiotic and glutathione metabolic processes as well as developmental processes (BMP, FGF signaling) in both sexes, while other pathways were exclusive to females or males. Glutathione S-transferase genes were further validated by qPCR showing upregulation of gstD4, gstD5 and gstD8 in respiratory tracts of females, while gstD8 was downregulated and gstD5 unchanged in males. ROS levels were increased in airways after CS. Exposure to CS further resulted in higher larval mortality, lower larval-pupal transition, and hatching rates in males only as compared to air-exposed controls.
Taken together, early life CS induces airway epithelial stress responses and dysregulates pathways involved in the fly's branching morphogenesis as well as in mammalian lung development. CS further affected fitness and development in a highly sex-specific manner.
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•Early life exposure to cigarette smoke (CS) is related to later airway diseases.•In D. melanogaster larval airways CS induces an oxidative stress response.•CS sex-specifically deregulates airway developmental and immune pathways.•This is connected to higher mortality until adulthood in male flies only.•The model offers a novel platform to study how early life CS links to airway disease.
According to the hygiene hypothesis, infections in early life protect from allergic diseases. However, in earlier studies surrogate measures of infection rather than clinical infections were ...associated with decreased frequencies of atopic diseases. Exposure to infection indicating sub-clinical infection rather than clinical infection might protect from atopic diseases.
to investigate whether exposure to acute respiratory infections within pregnancy and the first year of life is associated with atopic conditions at age 5-14 years and to explore when within pregnancy and the first year of life this exposure is most likely to be protective.
Historical cohort study: Population level data on acute respiratory infections from the routine reporting system of the former German Democratic Republic were linked with individual data from consecutive surveys on atopic diseases in the same region (n = 4672). Statistical analyses included multivariate logistic regression analysis and polynomial distributed lag models.
High exposure to acute respiratory infection between pregnancy and age one year was associated with overall reduced odds of asthma, eczema, hay fever, atopic sensitization and total IgE. Exposure in the first 9 months of life showed the most pronounced effect. Adjusted odds ratio's for asthma, hay fever, inhalant sensitization and total IgE were statistical significantly reduced up to around half.
Exposure to respiratory infection (most likely indicating sub-clinical infection) within pregnancy and the first year of life may be protective in atopic diseases development. The post-natal period thereby seems to be particularly important.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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).
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.
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