Laminin α4 contributes to airway remodeling and inflammation in asthma.

Airway inflammation and remodeling are characteristic features of asthma, with both contributing to airway hyperresponsiveness (AHR) and lung function limitation. Airway smooth muscle (ASM) accumulation and extracellular matrix deposition are characteristic features of airway remodeling, which may contribute to persistent AHR. Laminins containing the α2-chain contribute to characteristics of ASM remodeling in vitro and AHR in animal models of asthma. The role of other laminin chains, including the laminin α4 and α5 chains, which contribute to leukocyte migration in other diseases, is currently unknown. The aim of the current study was to investigate the role of these laminin chains in ASM function and in AHR, remodeling, and inflammation in asthma. Expression of both laminin α4 and α5 was observed in the human and mouse ASM bundle. In vitro, laminin α4 was found to promote a pro-proliferative, pro-contractile, and pro-fibrotic ASM cell phenotype. In line with this, treatment with laminin α4 and α5 function-blocking antibodies reduced allergen-induced increases in ASM mass in a mouse model of allergen-induced asthma. Moreover, eosinophilic inflammation was reduced by the laminin α4 function-blocking antibody as well. Using airway biopsies from healthy subjects and asthmatic patients, we found inverse correlations between ASM α4-chain expression and lung function and AHR, whereas eosinophil numbers correlated positively with expression of laminin α4 in the ASM bundle. This study, for the first time, indicates a prominent role for laminin α4 in ASM function and in inflammation, AHR, and remodeling in asthma, whereas the role of laminin α5 is more subtle.

Dual role of YM1+ M2 macrophages in allergic lung inflammation.

Alternatively activated (M2 or YM1+) macrophages have been associated with the development of asthma but their contribution to disease initiation and progression remains unclear. To assess the therapeutic potential of modulating these M2 macrophages, we have studied inhibition of M2 polarisation during and after development of allergic lung inflammation by treating with cynaropicrin, a galectin-3 pathway inhibitor. Mice that were treated with this inhibitor of M2 polarisation during induction of allergic inflammation developed less severe eosinophilic lung inflammation and less collagen deposition around airways, while the airway α-smooth muscle actin layer was unaffected. When we treated with cynaropicrin after induction of inflammation, eosinophilic lung inflammation and collagen deposition were also inhibited though to a lesser extent. Unexpectedly, both during and after induction of allergic inflammation, inhibition of M2 polarisation resulted in a shift towards neutrophilic inflammation. Moreover, airway hyperresponsiveness was worse in mice treated with cynaropicrin as compared to allergic mice without inhibitor. These results show that M2 macrophages are associated with remodeling and development of eosinophilic lung inflammation, but prevent development of neutrophilic lung inflammation and worsening of airway hyperresponsiveness. This study suggests that macrophages contribute to determining development of eosinophilic or neutrophilic lung inflammation in asthma.

What establishes an excellent nurse? A focus group and Delphi panel approach.

BACKGROUND: Over the past few years, the complexity of the health care system in which nurses are required to practice has increased considerably, magnifying the need for excellent professionals with a specific set of knowledge, skills and attitudes. However, the characteristics that distinguish an excellent nurse have not yet been clarified. The aim of this study was to determine nurses' perspectives regarding characteristics associated with an excellent nurse in order to elicit a conceptual profile. METHOD: A focus group design followed by Delphi panel content validation was utilized. Information regarding nurses' perspectives was derived from six focus group discussions comprising 19 nurses involved in hospital practice and 24 nurses with experience in mental health care. The analysis of the focus group discussions resulted in nine domains whereby content validity was achieved with contributions from a Delphi panel survey with 26 professionals. RESULTS: As determined by the survey, a combination of these specified aspects characterize an excellent nurse: analytical, communicative, cooperative, coordinating, disseminates knowledge, empathic, evidence-driven, innovative and introspective. CONCLUSION: Determining what establishes an excellent nurse according to experienced nurses is valuable as this information can influence the broadening curriculum for educating future nurses to meet the needs in the professional field, contributing to the quality of care. This conceptual profile can be used as a reference guide for supervisors and professionals to personally improve their clinical practice as well as for education.

Sexual maturation protects against development of lung inflammation through estrogen.

Increasing levels of estrogen and progesterone are suggested to play a role in the gender switch in asthma prevalence during puberty. We investigated whether the process of sexual maturation in mice affects the development of lung inflammation in adulthood and the contributing roles of estrogen and progesterone during this process. By inducing ovalbumin-induced lung inflammation in sexually mature and immature (ovariectomized before sexual maturation) adult mice, we showed that sexually immature adult mice developed more eosinophilic lung inflammation. This protective effect of "puberty" appears to be dependent on estrogen, as estrogen supplementation at the time of ovariectomy protected against development of lung inflammation in adulthood whereas progesterone supplementation did not. Investigating the underlying mechanism of estrogen-mediated protection, we found that estrogen-treated mice had higher expression of the anti-inflammatory mediator secretory leukoprotease inhibitor (SLPI) and lower expression of the proasthmatic cytokine IL-33 in parenchymal lung tissue and that their expressions colocalized with type II alveolar epithelial cells (AECII). Treating AECII directly with SLPI significantly inhibited IL-33 production upon stimulation with ATP. Our data suggest that estrogen during puberty has a protective effect on asthma development, which is accompanied by induction of anti-inflammatory SLPI production and inhibition of proinflammatory IL-33 production by AECII.

Distinct macrophage phenotypes in allergic and nonallergic lung inflammation.

Chronic exposure to farm environments is a risk factor for nonallergic lung disease. In contrast to allergic asthma, in which type 2 helper T cell (Th2) activation is dominant, exposure to farm dust extracts (FDE) induces Th1/Th17 lung inflammation, associated with neutrophil infiltration. Macrophage influx is a common feature of both types of lung inflammation, allergic and nonallergic. However, macrophage functions and phenotypes may vary according to their polarized state, which is dependent on the cytokine environment. In this study, we aimed to characterize and quantify the lung macrophage populations in two established murine models of allergic and nonallergic lung inflammation by means of fluorescence-activated cell sorting and immunohistochemistry. We demonstrated that, whereas in allergic asthma M2-dominant macrophages predominated in the lungs, in nonallergic inflammation M1-dominant macrophages were more prevalent. This was confirmed in vitro using a macrophage cell line, where FDE exerted a direct effect on macrophages, inducing M1-dominant polarization. The polarization of macrophages diverged depending on the exposure and inflammatory status of the tissue. Interfering with this polarization could be a target for treatment of different types of lung inflammation.

Characterization of macrophage phenotypes in three murine models of house-dust-mite-induced asthma.

In asthma, an important role for innate immunity is increasingly being recognized. Key innate immune cells in the lungs are macrophages. Depending on the signals they receive, macrophages can at least have an M1, M2, or M2-like phenotype. It is unknown how these macrophage phenotypes behave with regard to (the severity of) asthma. We have quantified the phenotypes in three models of house dust mite (HDM-)induced asthma (14, 21, and 24 days). M1, M2, and M2-like phenotypes were identified by interferon regulatory factor 5 (IRF5), YM1, and IL-10, respectively. We found higher percentages of eosinophils in HDM-exposed mice compared to control but no differences between HDM models. T cell numbers were higher after HDM exposure and were the highest in the 24-day HDM protocol. Higher numbers of M2 macrophages after HDM correlated with higher eosinophil numbers. In mice with less severe asthma, M1 macrophage numbers were higher and correlated negatively with M2 macrophages numbers. Lower numbers of M2-like macrophages were found after HDM exposure and these correlated negatively with M2 macrophages. The balance between macrophage phenotypes changes as the severity of allergic airway inflammation increases. Influencing this imbalanced relationship could be a novel approach to treat asthma.