American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Feb 2023
Crosstalk Between CD4+ T Cells and Airway Smooth Muscle in Pediatric Obesity-related Asthma.
Rationale: Pediatric obesity-related asthma is a nonatopic asthma phenotype with high disease burden and few effective therapies. RhoGTPase upregulation in peripheral blood T helper (Th) cells is associated with the phenotype, but the mechanisms that underlie this association are not known. Objectives: To investigate the mechanisms by which upregulation of CDC42 (Cell Division Cycle 42), a RhoGTPase, in Th cells is associated with airway smooth muscle (ASM) biology. ⋯ Compared with coculture with healthy-weight ASM, obese asthma Th cell coculture with obese ASM was positively enriched for genes and proteins involved in actin cytoskeleton organization, transmembrane receptor protein kinase signaling, and cell mitosis, and negatively enriched for extracellular matrix organization. Targeted gene evaluation revealed upregulation of IFNG, TNF (tumor necrosis factor), and Cluster of Differentiation 247 (CD247) among Th cell genes, and of Ak strain transforming (AKT), Ras homolog family member A (RHOA), and CD38, with downregulation of PRKCA (Protein kinase C-alpha), among smooth muscle genes. Conclusions: Obese asthma Th cells have uninhibited chemotaxis and are more adherent to obese ASM, which is associated with upregulation of genes and proteins associated with smooth muscle proliferation and reciprocal nonatopic Th cell activation.
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Am. J. Respir. Crit. Care Med. · Feb 2023
Heterogeneity of Airway Smooth Muscle Remodelling in Asthma.
Rationale: Ventilatory defects in asthma are heterogeneous and may represent the distribution of airway smooth muscle (ASM) remodeling. Objectives: To determine the distribution of ASM remodeling in mild-severe asthma. Methods: The ASM area was measured in nine airway levels in three bronchial pathways in cases of nonfatal (n = 30) and fatal asthma (n = 20) and compared with control cases without asthma (n = 30). ⋯ Using mean data, 44% of all asthma cases were classified as having no ASM remodeling in either the large or small airway despite a three- to 10-fold increase in the number of airways with ASM remodeling and 81% of asthma cases having ASM remodeling in at least one large and small airway. Conclusions: ASM remodeling is related to asthma severity but is heterogeneous within and between individuals and may contribute to the heterogeneous functional defects observed in asthma. These findings support the need for patient-specific targeting of ASM remodeling.