Corticosteroid Insensitivity Persists in the Absence of STAT1 Signaling in Severe Allergic Airway Inflammation

Corticosteroid insensitivity in asthma limits the ability to effectively manage severe asthma, which is characterized by persistent airway inflammation, airway hyperresponsiveness (AHR), and airflow obstruction despite corticosteroid treatment. Recent reports indicate that corticosteroid insensitivity is associated with increased interferon-gamma (IFN-g) levels and T-helper (Th) 1 lymphocyte infiltration in severe asthma. Signal Transducer and Activator of Transcription 1 (STAT1) activation by IFN-g is a key signaling pathway in Th1 inflammation, however its role in the context of severe allergic airway inflammation and corticosteroid sensitivity remains unclear. In the present study, we challenged wild type (WT) and Stat1-/- mice with mixed allergens (MA) augmented with c-di-GMP, an inducer of Th1 cell infiltration with increased eosinophils, neutrophils, Th1, Th2, and Th17 cells. Compared to WT mice, Stat1-/- had reduced neutrophils, Th1 and Th17 cell infiltration. To evaluate corticosteroid sensitivity, mice were treated with either vehicle, 1 or 3 mg/kg fluticasone propionate (FP). Corticosteroid significantly reduced eosinophil infiltration and cytokine levels in both c-di-GMP + MA-challenged WT and Stat1-/- mice. However, histological and functional analyses show that corticosteroids did not reduce airway inflammation, epithelial mucous cell abundance, airway smooth muscle mass, and AHR in c-di-GMP + MA-challenged WT or Stat1-/- mice. Collectively, our data suggest that increased Th1 inflammation is associated with a decrease in corticosteroid sensitivity. However, increased airway pathology and AHR persist in the absence of STAT1 indicate corticosteroid insensitivity in structural airway cells is a STAT1 independent process.

The effects of secondhand smoke on respiratory pathology, sensitization and development of allergic diseases in young children (literature review)

The prevalence of active smoking in Ukraine significantly exceeds the worldwide average, which is certainly a risk factor for children to be exposed to secondhand smoke. The article provides literature data and presents a modern view on the problem of secondhand tobacco smoke impact on the child population. In pediatric practice, the pathological impact of secondhand smoke on the child’s health is significant at the stage of its fetal development. Historical data convincingly prove the connection between the antenatal effect of secondhand smoke and the increased risk of perinatal losses and risks of pregnancy — miscarriage, stillbirth, and premature birth. As early as the 1960s and 1970s, scientific evidence was obtained for an association between the effects of tobacco smoke and the risk of sudden infant death syndrome. Children are most vulnerable to the negative effects of tobacco smoke at an early age because they have closer and longer contact with their parents, especially their mothers. Many studies have found an association between the effects of secondhand smoke and airway pathology (bronchitis, pneumonia), as well as an increase in the severity of respiratory syncytial viral infection (bronchiolitis). Numerous literature data indicate an association between the effect of passive smoking and the frequency and severity of oral cavity (dental caries) and middle ear (recurrent and chronic otitis, middle ear effusion) pathology. Many studies have shown the effects of secondhand smoke on the development and severity of bronchial asthma in children, but scientific data on the causal relationship of tobacco smoke with other allergic diseases (atopic dermatitis, allergic rhinitis, and food allergies), which are common in young children and preceded bronchial asthma in the "atopic march, are more limited and contradictory. The literature was searched using the PubMed database.

Multiple breath washout: measuring early manifestations of lung pathology

The multiple breath washout (MBW) test measures the efficiency of gas mixing in the lungs and has gained significant interest over the past 20 years. MBW outcomes detect early lung function impairment and peripheral airway pathology, through its main outcome measure lung clearance index (LCI). LCI measures the number of lung turnovers required to washout an inert tracer gas. MBW is performed during normal (tidal) breathing, making it particularly suitable for young children or those who have trouble performing forced manoeuvres. Additionally, research in chronic respiratory disease populations has shown that MBW can detect acute clinically relevant changes before conventional lung function tests, such as spirometry, thus enabling early intervention. The development of technical standards for MBW and commercial devices have allowed MBW to be implemented in clinical research and potentially routine clinical practice. Although studies have summarised clinimetric properties of MBW indices, additional research is required to establish the clinical utility of MBW and, if possible, shorten testing time. Sensitive, feasible measures of early lung function decline will play an important role in early intervention for people living with respiratory diseases.Educational aimTo describe the multiple breath washout test, its applications to lung pathology and respiratory disease, as well as directions for future research.

Large airway complications in COVID-19 pneumonia

COVID-19 pneumonia can cause respiratory failure which requires specialist management. However the inflammatory nature of the condition and the interventions necessary to manage these patients such as endotracheal intubation and tracheostomy can lead to large airway pathology which may go unrecognised. We describe five of the 44 (11%) consecutive patients referred to our specialist ARDS team between April and June 2020 with confirmed COVID-19 pneumonia who developed diverse large airway pathology which comprised of: supraglottic oedema, tracheal tear, tracheal granulation tissue formation, bronchomalacia, and tracheal diverticulum. Large airway pathology may be underappreciated in severely ill patients with COVID-19 pneumonia and should be considered in patients with unexplained air leak, prolonged need for mechanical ventilatory support, and repeated failed extubation or decannulation. If suspected, such patients should be managed by a team with expertise in large airway intervention and early specialist advice should be sought.

Fetal Growth Restriction and Asthma: Is the Damage Done?

Trajectories of airway remodeling and functional impairment in asthma are consistent with the notion that airway pathology precedes or coincides with the onset of asthma symptoms and may be present at birth. An association between intrauterine growth restriction (IUGR) and asthma development has also been established, and there is value in understanding the underlying mechanism. This review considers airway pathophysiology as a consequence of IUGR that increases susceptibility to asthma.

Semaphorin 3E deficiency dysregulates dendritic cell functions: In vitro and in vivo evidence

Regulation of dendritic cell functions is a complex process in which several mediators play diverse roles as a network in a context-dependent manner. The precise mechanisms underlying dendritic cell functions have remained to be addressed. Semaphorins play crucial roles in regulation of various cell functions. We previously revealed that Semaphorin 3E (Sema3E) contributes to regulation of allergen-induced airway pathology partly mediated by controlling recruitment of conventional dendritic cell subsets in vivo, though the underlying mechanism remained elusive. In this study, we investigate the potential regulatory role of Sema3E in dendritic cells. We demonstrated that bone marrow-derived dendritic cells differentiated from Sema3e-/- progenitors have an enhanced migration capacity both at the baseline and in response to CCL21. The enhanced migration ability of Sema3E dendritic cells was associated with an overexpression of the chemokine receptor (CCR7), elevated Rac1 GTPase activity and F-actin polymerization. Using a mouse model of allergic airway sensitization, we observed that genetic deletion of Sema3E leads to a time dependent upregulation of CCR7 on CD11b+ conventional dendritic cells in the lungs and mediastinal lymph nodes. Furthermore, aeroallergen sensitization of Sema3e-/- mice lead to an enhanced expression of PD-L2 and IRF-4 as well as enhanced allergen uptake in pulmonary CD11b+ DC, compared to wild type littermates. Collectively, these data suggest that Sema3E implicates in regulation of dendritic cell functions which could be considered a basis for novel immunotherapeutic strategies for the diseases associated with defective dendritic cells in the future.

Aging Regulates Post-Viral Asthmatic Airway Pathology

Asthma is a common chronic disease of childhood, but for unknown reasons disease activity sometimes subsides as children mature. To understand why, we exposed mice across a range of ages to viral and allergic triggers of asthma exacerbations and airway pathology. We found that pathology induced by Sendai virus (SeV) or influenza A virus (IAV) occurred selectively in juvenile mice in a microbiome-independent manner, while the same phenotypes induced by allergens were insensitive to age. Age-specific responses to SeV included a juvenile bias towards type-2 airway inflammation that emerged early in infection and was lost with maturation. With aging, we observed progressive transcriptional changes to alveolar macrophages (AMs) including the acquisition of high-level MHC-II expression. Importantly, depleting AMs canceled the protective effects of maturity on post-viral airway pathology. Thus, aging of the lung-immune microenvironment influences chronic outcomes of respiratory viral infection and may help to explain childhood asthma remission.