Activin and transforming growth factor-beta signaling pathways are activated after allergen challenge in mild asthma.

BACKGROUND: Both transforming growth factor (TGF)-beta(1) and activin-A have been implicated in airway remodeling in asthma, but the modulation of their specific signaling pathways after disease activation remains undefined. OBJECTIVE: To define the expression kinetics of TGF-beta(1), activin-A ligands, and follistatin (a natural activin inhibitor), their type I and type II receptors (activin-like kinase[ALK]-1, ALK-5, ALK-4, TbetaRII, and ActRIIA/RIIB) and activation of signaling (via phosphorylated (p) Smad2), in the asthmatic airway after allergen challenge. METHODS: Immunohistochemistry was performed on bronchial biopsies from 15 mild atopic patients with asthma (median age, 25 years; median FEV(1)% predicted, 97%) at baseline and 24 hours after allergen inhalation. Functional effects of activin-A were evaluated by using cultured normal human bronchial epithelial (NHBE) cells. RESULTS: pSmad2(+) epithelial cells increased at 24 hours (P = .03), and pSmad2 was detected in submucosal cells. No modulation of activin-A, follistatin, or TGF-beta(1) expression was demonstrated. Activin receptor(+) cells increased after allergen challenge: ALK-4 in epithelium (P = .04) and submucosa (P = .04), and ActRIIA in epithelium (P = .01). The TGF-beta receptor ALK-5 expression was minimal in the submucosa at baseline and after challenge and was downregulated in the epithelium after challenge (P = .02), whereas ALK-1 and TbetaRII expression in the submucosa increased after allergen challenge (P = .03 and P = .004, respectively). ALK-1 and ALK-4 expression by T cells was increased after allergen challenge. Activin-A induced NHBE cell proliferation, was produced by NHBE cells in response to TNF-alpha, and downregulated TNF-alpha and IL-13-induced chemokine production by NHBE cells. CONCLUSION: Both TGF-beta and activin signaling pathways are activated on allergen provocation in asthma. Activin-A may contribute to resolution of inflammation.

Basal expression of bone morphogenetic protein receptor is reduced in mild asthma.

RATIONALE: Despite increasing recognition of bone morphogenetic protein (BMP) signaling in tissue remodeling, the expression pattern of ligands and signaling pathways remain undefined in the asthmatic airway. OBJECTIVES: To determine expression of BMP ligands (BMP-2, BMP-4, and BMP-7) and type I and type II receptors (ALK-2, ALK-3, ALK-6, and BMPRII) as well as evidence for activation of BMP signaling via detection of phosphorylated Smad1/5 (pSmad1/5) expression in asthmatic airways at baseline (compared with nonasthmatic controls), and after allergen challenge. METHODS: Bronchial biopsies were obtained from 6 nonasthmatic control volunteers, and 15 atopic patients with asthma (median age, 25 yr; median FEV(1)% predicted, 97%) at baseline, then at 24 hours and 7 days after allergen challenge. Expression of BMP ligands, receptors, and signaling was analyzed using immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: BMP ligand expression did not differ between asthmatic and control airways at baseline. Compared with the normal airway, there was significant down-regulation of ALK-2 (P = 0.001), ALK-6 (P = 0.0009), and BMPRII (P = 0.009) expression in asthma. Allergen challenge was associated with marked and sustained up-regulation of BMP-7 in airway epithelium (P = 0.017) and infiltrating inflammatory cells (P = 0.071) (predominantly in eosinophils, but also CD4(+) T cells, mast cells, and macrophages). Up-regulation of pSmad1/5 expression (P = 0.031), ALK-2 (P = 0.002), and ALK-6 (P < 0.001) was observed indicating active signaling. CONCLUSIONS: BMP receptor expression is down-regulated in the asthmatic airway, which may impede repair responses. Allergen provocation increases expression of the regulatory ligand BMP-7, activates BMP signaling, and increases receptor expression, all of which may contribute to repair and control of inflammation.

Remodeling and airway hyperresponsiveness but not cellular inflammation persist after allergen challenge in asthma.

RATIONALE: Airway hyperresponsiveness (AHR) increases up to 2 weeks after allergen inhalational challenge of subjects with asthma who show a late-phase asthmatic reaction (dual responders). Cellular inflammation and airway remodeling are increased 24 hours after allergen challenge. OBJECTIVES: To determine whether persistence of increased AHR is associated with persistent activation of remodeling and enhanced inflammation. METHODS: Fiberoptic bronchoscopy was performed at baseline and at 24 hours and 7 days after allergen inhalational challenge of dual responders with mild-moderate asthma. At each time point, AHR, spirometry, and expression of tenascin (extracellular matrix protein), procollagen I, procollagen III, and heat shock protein (HSP)-47 (markers of collagen synthesis), and alpha-smooth muscle actin (myofibroblasts) were evaluated as markers of activation of airway remodeling, together with numbers of mucosal major basic protein-positive eosinophils, CD68(+) macrophages, CD3(+), CD4(+), CD8(+) T cells, elastase-positive neutrophils, and tryptase-positive mast cells. MEASUREMENTS AND MAIN RESULTS: AHR was increased from baseline at 24 hours and 7 days after allergen challenge. Reticular basement membrane tenascin expression was elevated at 24 hours and returned to baseline levels at 7 days. Reticular basement membrane procollagen III expression was significantly elevated at 7 days. Expression of procollagen I, HSP-47, and alpha-smooth muscle actin were all higher at 7 days compared with 24 hours. At 24 hours, eosinophil, macrophage, neutrophil, and CD3(+) T cells were increased but had returned to baseline by 7 days. CONCLUSIONS: In dual responders with asthma, the 24-hour increase in airway wall cellular inflammation after allergen challenge resolves by 7 days, whereas the increases in AHR and markers of remodeling persist.