The coronavirus disease 2019 (COVID-19) pandemic, caused by SARS-CoV-2, has caused severe disease outcomes and widespread infections not seen in terms of its case fatality rate and global economic ...impact since the 1918 to 1919 Spanish flu, with the latter leading to 675,000 deaths in the United States (US) (50 million worldwide) (1). The US currently has the largest number of SARS-CoV-2 infections in the world, with tremendous health, economic, and social ramifications, including closing of schools, businesses, and all public gatherings in order to maximize social distancing and prevent virus spread. Here, we address the major impact of the COVID-19 pandemic on biomedical research, the challenges created by the COVID-19 pandemic for research-intensive institutions, and what investigators can do to maintain some level of research activity while keeping their coworkers and trainees safe and engaged. While research unrelated to COVID-19 has slowed and remote work has placed significant constraints on the efficiency of operations, research on COVID-19 has exploded with energy and urgency.
Among patients with moderate-to-severe asthma who were receiving a range of inhaled glucocorticoid maintenance therapies, the risk of severe asthma exacerbation was significantly lower with as-needed ...use of a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide than with albuterol alone.
Among patients with asthma, heterogeneity exists regarding the pattern of airway inflammation and response to treatment, prompting the necessity of recognizing specific phenotypes. Based on the ...analysis of inflammatory cell counts in induced sputum, asthmatic patients can be classified into 4 unique phenotypes: eosinophilic asthma, neutrophilic asthma, mixed granulocytic asthma, and paucigranulocytic asthma (PGA). PGA is an asthma phenotype with no evidence of increased numbers of eosinophils or neutrophils in sputum or blood and in which anti-inflammatory therapies are ineffective at controlling symptoms. Although underinvestigated, PGA is the most common asthma phenotype in patients with stable asthma. However, PGA is sometimes underestimated because of the exclusive reliance on induced sputum cell counts, which are variable among cohorts of studies, prompting the necessity of developing improved biomarkers. Importantly, investigators have reported that inhaled corticosteroids had a limited effect on airway inflammatory markers in patients with PGA and therefore defining PGA as a potentially “steroid-insensitive” phenotype that requires exploration of alternative therapies. PGA manifests as an uncoupling of airway obstruction from airway inflammation that can be driven by structural changes within the airways, such as airway smooth muscle tissue hypertrophy. Animal models provide evidence that processes evoking airway hyperresponsiveness and airway smooth muscle thickening occur independent from inflammation and might be a consequence of a loss of negative homeostatic processes. Collectively, further understanding of PGA with a focus on the characterization, prevalence, clinical significance, and pathobiology derived from animal studies will likely provide precision therapies that will improve PGA clinical outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Publications utilizing precision cut lung slices (PCLS) steadily increased from the 1970's, with a significant increase in 2010, to tripling by 2023. PCLS have been used to study a vast array of ...pulmonary diseases and exposures to pathogens and toxicants to understand pathogenesis of disease but also to examine basic cellular mechanisms that underly lung biology. This Special Issue will highlight new, exciting, and novel research using PCLS, while acknowledging the substantial fund of knowledge that has been gained using this platform.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human respiratory syncytial virus (RSV) is a major cause of severe respiratory illness in children and susceptible adults. RSV blocks the development of the innate antiviral immune response and can ...grow to high titers in the respiratory tract. Here we demonstrate that immunostimulatory defective viral genomes (iDVGs) that are naturally generated during RSV replication are strong inducers of the innate antiviral response to RSV in mice and humans. In mice, RSV iDVGs stimulated the expression of antiviral genes, restricted viral replication, and prevented weight loss and lung inflammation. In human cells, the antiviral response to RSV iDVGs was dominated by the expression of IFN-λ1 over IFN-β and was driven by rapid intranuclear accumulation of the transcription factor IRF1. RSV iDVGs were detected in respiratory secretions of hospitalized patients, and their amount positively correlated with the level of expression of antiviral genes in the samples. Infection of explanted human lung tissue from different donors revealed that most humans can respond to RSV iDVGs and that the rate of accumulation of iDVGs during infection directly correlates with the quality of the antiviral response. Taken together, our data establish iDVGs as primary triggers of robust antiviral responses to RSV and provide the first evidence for an important biological role for naturally occurring iDVGs during a paramyxovirus infection in humans.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although 2 T-helper type 2 inflammation evokes airway hyperresponsiveness and narrowing, neutrophilic or pauci-immune asthma accounts for significant asthma morbidity. Viruses, toxicants, ...environmental tobacco smoke exposure, and bacterial infections induce asthma exacerbations mediated by neutrophilic inflammation or by structural cell (pauci-immune) mechanisms. Therapeutic challenges exist in the management of neutrophilic and pauci-immune phenotypes because both syndromes manifest steroid insensitivity. The recognition that neutrophil subsets exist and their functions are unique poses exciting opportunities to develop precise therapies. The conventional thought to target neutrophil activation or migration globally may explain why current drug development in neutrophilic asthma remains challenging.
The pathogenesis of asthma includes a complex interplay among airway inflammation, hyperresponsiveness, and remodeling. Current evidence suggests that airway structural cells, including bronchial ...smooth muscle cells, myofibroblasts, fibroblasts, and epithelial cells, mediate all three aspects of asthma pathogenesis. Although studies show a connection between airway remodeling and changes in bronchomotor tone, the relationship between the two remains unclear. Transforming growth factor β1 (TGF-β1), a growth factor elevated in the airway of patients with asthma, plays a role in airway remodeling and in the shortening of various airway structural cells. However, the role of TGF-β1 in mediating airway hyperresponsiveness remains unclear. In this review, we summarize the literature addressing the role of TGF-β1 in airway remodeling and shortening. Through our review, we aim to further elucidate the role of TGF-β1 in asthma pathogenesis and the link between airway remodeling and airway hyperresponsiveness in asthma and to define TGF-β1 as a potential therapeutic target for reducing asthma morbidity and mortality.
Precision Cut Lung Slices (PCLS) have emerged as a sophisticated and physiologically relevant ex vivo model for studying the intricacies of lung diseases, including fibrosis, injury, repair, and host ...defense mechanisms. This innovative methodology presents a unique opportunity to bridge the gap between traditional in vitro cell cultures and in vivo animal models, offering researchers a more accurate representation of the intricate microenvironment of the lung. PCLS require the precise sectioning of lung tissue to maintain its structural and functional integrity. These thin slices serve as invaluable tools for various research endeavors, particularly in the realm of airway diseases. By providing a controlled microenvironment, precision-cut lung slices empower researchers to dissect and comprehend the multifaceted interactions and responses within lung tissue, thereby advancing our understanding of pulmonary pathophysiology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glucocorticoid (GC) anti-inflammatory effects generally require a prolonged onset of action and involve genomic processes. Because of the rapidity of some of the GC effects, however, the concept that ...non-genomic actions may contribute to GC mechanisms of action has arisen. While the mechanisms have not been completely elucidated, the non-genomic effects may play a role in the management of inflammatory diseases. For instance, we recently reported that GCs ‘rapidly’ enhanced the effects of bronchodilators, agents used in the treatment of allergic asthma. In this review article, we discuss (i) the non-genomic effects of GCs on pathways relevant to the pathogenesis of inflammatory diseases and (ii) the putative role of the membrane GC receptor. Since GC side effects are often considered to be generated through its genomic actions, understanding GC non-genomic effects will help design GCs with a better therapeutic index.
GC genomic and non-genomic effects involve distinct mechanisms of action but play complementary roles in mediating the anti-inflammatory effects of GCs.
GCs are mostly used in asthma as a ‘controller’ therapy because of their delayed effects, but since GCs recently have been shown to ‘rapidly’ enhance the effects of bronchodilators, they could be used also as a ‘rescue’ therapy, especially in combination with β2 agonists.
Compelling evidence proposed the emerging role of (airway) structural cells as a major target for GC non-genomic effects that act through poorly understood, cell-specific mechanisms.
Both inflammatory pathways and non-inflammatory pathways such as calcium mobilization, muscle tone, and reactive oxygen species are targets for the GC non-genomic effects.
Designing a GC able to solely act through non-genomic pathways may prevent some of the GC side effects often engendered by GC genomic effects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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