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Seminars in Respiratory and Critical... Oct 2023While static mechanical forces govern resting lung volumes, dynamic forces determine tidal breathing, airflow, and changes in airflow and lung volume during normal and...
While static mechanical forces govern resting lung volumes, dynamic forces determine tidal breathing, airflow, and changes in airflow and lung volume during normal and abnormal breathing. This section will examine the mechanisms, measurement methodology, and interpretation of the dynamic changes in airflow and lung volume that occur in health and disease. We will first examine how the total work of breathing can be described by the parameters of the equation of motion, which determine the pressure required to move air into and out of the lung. This will include a detailed description of airflow characteristics and airway resistance. Next, we will review the changes in pressure and flow that determine maximal forced inspiration and expiration, which result in the maximal flow-volume loop and the clinically important forced expired volume in 1 second. We will also assess the mechanisms and interpretation of bronchodilator responsiveness, dynamic hyperinflation, and airways hyperresponsiveness.
Topics: Humans; Lung; Bronchodilator Agents
PubMed: 37429331
DOI: 10.1055/s-0043-1770058 -
Cell Jan 2024Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with...
Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1 expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.
Topics: Animals; Humans; Mice; Cytokines; Dermatitis, Atopic; Immunity, Innate; Inflammation; Lung; Lymphocytes; Sensory Receptor Cells
PubMed: 38134932
DOI: 10.1016/j.cell.2023.11.027 -
Nature Sep 2023Disruption of the lung endothelial-epithelial cell barrier following respiratory virus infection causes cell and fluid accumulation in the air spaces and compromises...
Disruption of the lung endothelial-epithelial cell barrier following respiratory virus infection causes cell and fluid accumulation in the air spaces and compromises vital gas exchange function. Endothelial dysfunction can exacerbate tissue damage, yet it is unclear whether the lung endothelium promotes host resistance against viral pathogens. Here we show that the environmental sensor aryl hydrocarbon receptor (AHR) is highly active in lung endothelial cells and protects against influenza-induced lung vascular leakage. Loss of AHR in endothelia exacerbates lung damage and promotes the infiltration of red blood cells and leukocytes into alveolar air spaces. Moreover, barrier protection is compromised and host susceptibility to secondary bacterial infections is increased when endothelial AHR is missing. AHR engages tissue-protective transcriptional networks in endothelia, including the vasoactive apelin-APJ peptide system, to prevent a dysplastic and apoptotic response in airway epithelial cells. Finally, we show that protective AHR signalling in lung endothelial cells is dampened by the infection itself. Maintenance of protective AHR function requires a diet enriched in naturally occurring AHR ligands, which activate disease tolerance pathways in lung endothelia to prevent tissue damage. Our findings demonstrate the importance of endothelial function in lung barrier immunity. We identify a gut-lung axis that affects lung damage following encounters with viral pathogens, linking dietary composition and intake to host fitness and inter-individual variations in disease outcome.
Topics: Animals; Humans; Mice; Apelin; Diet; Endothelial Cells; Endothelium; Epithelial Cells; Erythrocytes; Influenza, Human; Intestines; Leukocytes; Ligands; Lung; Orthomyxoviridae Infections; Pulmonary Alveoli; Receptors, Aryl Hydrocarbon
PubMed: 37587341
DOI: 10.1038/s41586-023-06287-y -
Presse Medicale (Paris, France : 1983) Sep 2023Bronchiectasis is a final common pathway of a wide variety of underlying conditions including infectious, autoimmune, allergic, genetic and inflammatory conditions.... (Review)
Review
Bronchiectasis is a final common pathway of a wide variety of underlying conditions including infectious, autoimmune, allergic, genetic and inflammatory conditions. Patients experience a chronic disease with variable clinical symptoms and course, but most experience cough, sputum production and recurrent exacerbations. Symptoms of bronchiectasis lead to poor quality of life and exacerbations are the major driver of morbidity and mortality. Patients are often chronically infected with bacteria with the most common being Pseudomonas aeruginosa and Haemophilus influenzae. Treatment of bronchiectasis includes standardised testing to identify the underlying cause with targeted treatment if immune deficiency, allergic bronchopulmonary aspergillosis or non-tuberculous mycobacterial infection, for example, are identified. Airway clearance is the mainstay of therapy for patients with symptoms of cough and sputum production. Frequently exacerbating patients may benefit from long term antibiotic or mucoactive therapies. Bronchiectasis is a heterogeneous disease and increasingly precision medicine approaches are advocated to target treatments most appropriately and to limit the emergence of antimicrobial resistance.
Topics: Bronchiectasis; Humans; Anti-Bacterial Agents; Quality of Life
PubMed: 37778637
DOI: 10.1016/j.lpm.2023.104174 -
Journal of Clinical Oncology : Official... Dec 2023Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3)...
HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy.
PURPOSE
Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor ()-mutated non-small-cell lung cancer (NSCLC).
METHODS
This phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data.
RESULTS
Enrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations.
CONCLUSION
After tumor progression with EGFR TKI therapy and PBC in patients with -mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Platinum; ErbB Receptors; Mutation; Protein Kinase Inhibitors
PubMed: 37689979
DOI: 10.1200/JCO.23.01476 -
Cureus Nov 2023Nasal congestion is a common issue stemming from various factors such as allergies and anatomical variations. Allergic rhinitis frequently leads to nasal congestion. The... (Review)
Review
Nasal congestion is a common issue stemming from various factors such as allergies and anatomical variations. Allergic rhinitis frequently leads to nasal congestion. The pathophysiology involves inflammation, swelling, and mucus production in the nasal mucosa. Multiple treatments are available, including oral phenylephrine, an over-the-counter or prescription option. However, the effectiveness and safety of phenylephrine have been subjects of debate. This systematic review aims to provide an updated perspective on the efficacy of oral phenylephrine versus placebo in addressing nasal congestion in adults. We conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, a systematic review involving searches on PubMed, Cochrane, and Scopus databases. Inclusion/exclusion criteria were defined to identify high-quality studies. The focus was on randomized controlled trials (RCTs) and case-control studies published in English between 1998 and 2023, involving adult populations. The interventions compared oral phenylephrine with placebo or standard care, with outcomes centering on changes in nasal congestion symptoms and nasal airway resistance. We identified four articles that met the criteria. These studies exhibited varied designs and populations. The findings consistently indicated that phenylephrine was not more effective than a placebo in relieving nasal congestion. This systematic review demonstrates that oral phenylephrine did not offer substantial relief from nasal congestion compared to a placebo in adults. The studies featured diverse designs, yet the prevailing conclusion was that phenylephrine's efficacy was limited. Safety assessments showed no life-threatening adverse events, with common side effects including headaches and mild discomfort. In summary, this systematic review indicates that oral phenylephrine is not significantly more effective than a placebo in alleviating nasal congestion in adults. Clinicians should explore alternative treatment options, considering the review's limitations. Additional research may be needed to clarify the role of oral phenylephrine in managing nasal congestion.
PubMed: 38125218
DOI: 10.7759/cureus.49074