In patients with mild asthma, as-needed budesonide-formoterol provided superior asthma-symptom control to as-needed terbutaline, assessed according to electronically recorded weeks with well-controlled asthma, but was inferior to budesonide maintenance therapy. Exacerbation rates with the two budesonide-containing regimens were similar and were lower than the rate with terbutaline. Budesonide-formoterol used as needed resulted in substantially lower glucocorticoid exposure than budesonide maintenance therapy. (Funded by AstraZeneca; SYGMA 1 ClinicalTrials.gov number, NCT02149199 .).
GM-CSF is a key mediator in smoke-induced airways inflammation, and its neutralization may have therapeutic implications in diseases such as COPD.
Recent data indicate that the proinflammatory cytokine, interleukin (IL)-17, stimulates certain effector functions of human macrophages. We evaluated whether IL-17 mediates allergen-induced accumulation of airway macrophages and, if so, whether such an effect relates to the control of macrophage recruitment and survival. BALB/c mice were sensitized and challenged with ovalbumin. Three hours before challenge an anti-mouse IL-17 mAb (a-IL-17) was administered. Sampling was conducted 24 h after the allergen challenge. In vitro chemotaxis assay for blood monocytes and culture of airway macrophages, immunocytochemistry for Fas-antigen, and matrix metalloproteinase-9 (MMP-9) were used to determine the effect of IL-17 on the recruitment, survival, and activity of airway macrophages. A-IL-17 reduced the number of airway neutrophils and macrophages after allergen challenge. In vitro, recombinant IL-17 induced migration of blood monocytes and prolonged survival of airway macrophages. A-IL-17 also increased the expression of Fas-antigen in airway macrophages in vivo. Finally, the expression of MMP-9 by airway neutrophils and macrophages in vivo was downregulated by a-IL-17. This study indicates that endogenous IL-17 mediates the accumulation of macrophages during allergen-induced airway inflammation. IL-17 exerts its effects by acting directly on airway macrophages by promoting their recruitment and survival. Furthermore, IL-17 is involved in controlling the proteolytic activity of macrophages and neutrophils in allergen-induced airway inflammation.
It is known that interleukin (IL)-23, an IL-12-family cytokine, can be released by certain antigen-presenting cells in response to bacterial pathogens. Recent in vitro studies indicate that this cytokine stimulates a unique subset of CD4 cells, the T helper cell (Th)17 subset, to produce and release the proinflammatory cytokine IL-17. However, it has not been known whether this is an action of IL-23 per se that has bearing for the early innate response in lungs in vivo and whether there is an IL-23-responsive population of IL-17-producing CD4 cells in the bronchoalveolar space. We now present evidence that IL-23 can be involved in the early innate response to both gram-negative and gram-positive bacterial products in the lungs: Recombinant IL-23 protein per se accumulates inflammatory cells in the bronchoalveolar space in part via endogenous production of IL-17, and this IL-17 production occurs locally in IL-23-responsive CD4 cells. This IL-17 response to IL-23 occurs without any pronounced impact on Th1/Th2 polarization. Moreover, recombinant IL-23 protein increases the local MMP-9 activity, which is generated by neutrophils mainly. CD4 cells in the lungs may thus respond to IL-23 from antigen-presenting cells exposed to gram-negative and gram-positive pathogens and thereby reinforce the early innate response. These findings support that IL-23 and IL-17 form a functionally relevant "immunological axis" in the lungs in vivo.
Research Summary We administered a survey experiment to a national sample of 1068 U.S. adults in April 2020 to determine the factors that shape support for various policing tactics in the midst of the COVID‐19 pandemic. Respondents were sharply divided in their views about pandemic policing tactics and were least supportive of policies that might limit public access to officers or reduce crime deterrence. Information about the health risks to officers, but not to inmates, significantly increased support for “precautionary” policing, but not for “social distance” policing. The information effect was modest, but may be larger if the information came from official sources and/or was communicated on multiple occasions. Other factors that are associated with attitudes toward pandemic policing include perceptions of procedural justice, altruistic fear, racial resentment, and authoritarianism. Policy Implications When considered together with other evidence, one clear takeaway from our study is that the public values police patrols and wants officers on call, even during pandemics. Another is that people who believe the police are procedurally just are more willing to trust officers in times of crisis and to empower them to enforce new laws, such as social distancing ordinances. Our results thus support continued procedural justice training for officers. A third takeaway is that agencies must proactively communicate with the public about the risks their officers face when responding to public health crises or natural disasters, in addition to how they propose to mitigate those risks. They must also be amenable to adjusting in response to community feedback.
Budesonide/formoterol maintenance and reliever therapy provided more effective asthma control, including a prolonged time to first severe asthma exacerbation, than budesonide/formoterol plus terbutaline and was well tolerated. Budesonide/formoterol maintenance and reliever therapy also improved lung function and asthma symptoms.
Naive CD4 cells are capable of integrating signals from antigen-activated cells of the innate immune system and differentiating into effector CD4 cells, also termed T helper (Th) cells. According to the traditional paradigm explaining adaptive CD4 cell responses, there are two subsets of Th cells: the Th-1 and Th-2 subset. Each of these subsets undergoes a distinct differentiation pathway (a pathway that is characterized by a unique profile of cytokine production and has specific immunoregulatory functions). However, recent studies in mouse models have forwarded evidence of a third subset of Th cells: the Th-17 subset. As indicated predominantly in studies on mice, the Th-17 subset is characterized by an ability to produce the neutrophil-mobilizing cytokine IL-17 in response to stimulation with the cytokine IL-23, an IL-12-related cytokine released from antigen-presenting cells. There is now a growing body of evidence from animal models that the Th-17 subset plays an important role in host defence in the lungs and other organs. Altered IL-17 levels have also been demonstrated in human patients with asthma, exacerbations of cystic fibrosis or following lung transplantation. There is now also evidence that the Th-17 subset is functionally distinct from the Th-2 subset but little is known of the functional inter-relationship between the Th-1 and Th-17 cell subsets; this is particularly true in human lungs. It has been proposed that the Th-17 subset plays a unique role by linking the arms of innate and adaptive immunity. Thus, an improved understanding of the human correlate to the Th-17 subset may reveal new targets for pharmacotherapy against lung disorders that are characterized by aberrant innate responses in host defense.
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