The role of γδ T cells in airway epithelial injury and bronchial responsiveness after chlorine gas exposure in mice

BACKGROUND: Acute exposure to chlorine (Cl(2)) gas causes epithelial injury and airway dysfunction. γδ T cells are present in the mucosal surface of the airways and may contribute to the injury/repair response of the epithelium. METHODS: C57Bl/6J (wild type) and TCR-δ(-/- )mice exposed to Cl(2 )(400 ppm) for 5 minutes underwent measurements of airway responses to i.v. methacholine (MCh) at 1, 3, and 5 days after exposure. Bronchoalveolar lavage was performed to determine epithelial and leukocyte counts, and protein content. Tissue repair was assessed by proliferating cell nuclear antigen (PCNA) immunoreactivity and by expression of keratinocyte growth factor (KGF) mRNA by real-time PCR. RESULTS: Wild type mice developed a greater degree of airway hyperresponsiveness to MCh at 1 day post exposure to Cl(2 )compared with TCR-δ(-/- )mice. Epithelial cell counts in BAL after Cl(2 )exposure were greater in TCR-δ(-/- )mice, but macrophages showed a later peak and granulocyte numbers were lower in TCR-δ(-/- )than in wild type mice. Both groups had increased levels of total protein content in BAL after Cl(2 )exposure that resolved after 3 and 5 days, respectively. Epithelial proliferating cell nuclear antigen staining was increased at 1 and 3 days post exposure and was similar in the two groups. KGF mRNA was constitutively expressed in both groups and did not increase significantly after Cl(2 )but expression was lower in TCR-δ(-/- )mice. CONCLUSION: The severity of airway epithelial injury after Cl(2 )is greater in TCR-δ(-/- )mice but the inflammatory response and the change in airway responsiveness to methacholine are reduced. The rates of epithelial regeneration are comparable in both groups

Contribution of human hematopoietic stem cells to liver repair

Immune-deficient mouse models of liver damage allow examination of human stem cell migration to sites of damage and subsequent contribution to repair and survival. In our studies, in the absence of a selective advantage, transplanted human stem cells from adult sources did not robustly become hepatocytes, although some level of fusion or hepatic differentiation was documented. However, injected stem cells did home to the injured liver tissue and release paracrine factors that hastened endogenous repair and enhanced survival. There were significantly higher levels of survival in mice with a toxic liver insult that had been transplanted with human stem cells but not in those transplanted with committed progenitors. Transplantation of autologous adult stem cells without conditioning is a relatively safe therapy. Adult stem cells are known to secrete bioactive factors that suppress the local immune system, inhibit fibrosis (scar formation) and apoptosis, enhance angiogenesis, and stimulate recruitment, retention, mitosis, and differentiation of tissue-residing stem cells. These paracrine effects are distinct from the direct differentiation of stem cells to repair tissue. In patients at high risk while waiting for a liver transplant, autologous stem cell therapy could be considered, as it could delay the decline in liver function

Particulate Matter-Induced Lung Inflammation Increases Systemic Levels of PAI-1 and Activates Coagulation Through Distinct Mechanisms

Exposure of human populations to ambient particulate matter (PM) air pollution significantly contributes to the mortality attributable to ischemic cardiovascular events. We reported that mice treated with intratracheally instilled PM develop a prothrombotic state that requires the release of IL-6 by alveolar macrophages. We sought to determine whether exposure of mice to PM increases the levels of PAI-1, a major regulator of thrombolysis, via a similar or distinct mechanism. mice but was absent in mice treated with etanercept, a TNF-α inhibitor. Treatment with etanercept did not prevent the PM-induced tendency toward thrombus formation.Mice exposed to inhaled PM exhibited a TNF-α-dependent increase in PAI-1 and an IL-6-dependent activation of coagulation. These results suggest that multiple mechanisms link PM-induced lung inflammation with the development of a prothrombotic state

Stem cells in liver regeneration and therapy

The liver has adapted to the inflow of ingested toxins by the evolutionary development of unique regenerative properties and responds to injury or tissue loss by the rapid division of mature cells. Proliferation of the parenchymal cells, i.e. hepatocytes and epithelial cells of the bile duct, is regulated by numerous cytokine/growth-factor-mediated pathways and is synchronised with extracellular matrix degradation and restoration of the vasculature. Resident hepatic stem/progenitor cells have also been identified in small numbers in normal liver and implicated in liver tissue repair. Their putative role in the physiology, pathophysiology and therapy of the liver, however, is not yet precisely known. Hepatic stem/progenitor cells also known as “oval cells” in rodents have been implicated in liver tissue repair, at a time when the capacity for hepatocyte and bile duct replication is exhausted or experimentally inhibited (facultative stem/progenitor cell pool). Although much more has to be learned about the role of stem/progenitor cells in the physiology and pathophysiology of the liver, experimental analysis of the therapeutic value of these cells has been initiated. Transplantation of hepatic stem/progenitor cells or in vivo pharmacological activation of the pool of hepatic stem cells may provide novel modalities for the therapy of liver diseases. In addition, extrahepatic stem cells (e.g. bone marrow cells) are being investigated for their contribution to liver regeneration. Hepatic progenitor cells derived from embryonic stem cells are included in this review, which also discusses future perspectives of stem cell-based therapies for liver diseases

Exploring geographic differences in IgE response through network and manifold analyses

BACKGROUND: Component-resolved diagnostics allow detailed assessment of IgE sensitization to multiple allergenic molecules (component-specific IgEs, or c-sIgEs) and may be useful for asthma diagnosis. However, to effectively use component-resolved diagnostics across diverse settings, it is crucial to account for geographic differences. OBJECTIVE: We investigated spatial determinants of c-sIgE networks to facilitate development of diagnostic algorithms applicable globally. METHODS: We used multiplex component-resolved diagnostics array to measure c-sIgE to 112 proteins in an international collaboration of several studies: WASP (World Asthma Phenotypes; United Kingdom, New Zealand, Brazil, Ecuador, and Uganda), U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes; 7 European countries), and MAAS (Manchester Asthma and Allergy Study, a UK population-based birth cohort). Hierarchical clustering on low-dimensional representation of co-occurrence networks ascertained sensitization and c-sigE clusters across populations. Cross-country comparisons focused on a common subset of 18 c-sIgEs. We investigated sensitization networks across regions in relation to asthma severity. RESULTS: Sensitization profiles shared similarities across regions. For 18 c-sIgEs shared across study populations, the response structure enabled differentiation between different geographic areas and study designs, revealing 3 clusters: (1) Uganda, Ecuador, and Brazil, (2) U-BIOPRED children and adults, and (3) New Zealand, United Kingdom, and MAAS. Spectral clustering identified differences between clusters. We observed constant, almost parallel shifts between severe and nonsevere asthma in each country. CONCLUSIONS: Patterns of c-sIgE response reflect geographic location and study design. However, despite geographic differences in c-sIgE networks, there is a remarkably consistent shift between networks of subjects with nonsevere and severe asthma

Detrimental effects of albuterol on airway responsiveness requires airway inflammation and is independent of β-receptor affinity in murine models of asthma

<p>Abstract</p> <p>Background</p> <p>Inhaled short acting β2-agonists (SABA), e.g. albuterol, are used for quick reversal of bronchoconstriction in asthmatics. While SABA are not recommended for maintenance therapy, it is not uncommon to find patients who frequently use SABA over a long period of time and there is a suspicion that long term exposure to SABA could be detrimental to lung function. To test this hypothesis we studied the effect of long-term inhaled albuterol stereoisomers on immediate allergic response (IAR) and airway hyperresponsiveness (AHR) in mouse models of asthma.</p> <p>Methods</p> <p>Balb/C mice were sensitized and challenged with ovalbumin (OVA) and then we studied the IAR to inhaled allergen and the AHR to inhaled methacholine. The mice were pretreated with nebulizations of either racemic (RS)-albuterol or the single isomers (S)- and (R)-albuterol twice daily over 7 days prior to harvest.</p> <p>Results</p> <p>We found that all forms of albuterol produced a significant increase of IAR measured as respiratory elastance. Similarly, we found that AHR was elevated by albuterol. At the same time a mouse strain that is intrinsically hyperresponsive (A/J mouse) was not affected by the albuterol isomers nor was AHR induced by epithelial disruption with Poly-L-lysine affected by albuterol.</p> <p>Conclusions</p> <p>We conclude that long term inhalation treatment with either isomer of albuterol is capable of precipitating IAR and AHR in allergically inflamed airways but not in intrinsically hyperresponsive mice or immunologically naïve mice. Because (S)-albuterol, which lacks affinity for the β2-receptor, did not differ from (R)-albuterol, we speculate that isomer-independent properties of the albuterol molecule, other than β2-agonism, are responsible for the effect on AHR.</p