ORCID ID: 0000-0001-7054-794X (J.L.I.).
AbstractElastin synthesis and degradation in the airway and lung parenchyma contribute to airway mechanics, including airway patency and elastic recoil. IL-13 mediates many features of asthma pathobiology, including airway remodeling, but the effects of IL-13 on elastin architecture in the airway wall are not known. We hypothesized that IL-13 modulates elastin expression in airway fibroblasts from subjects with allergic asthma. Twenty-five subjects with mild asthma (FEV 1 , 89 6 3% predicted) and 30 normal control subjects (FEV 1 , 102 6 2% predicted) underwent bronchoscopy with endobronchial biopsy. Elastic fibers were visualized in airway biopsy specimens using Weigert's resorcin-fuchsin elastic stain. Airway fibroblasts were exposed to IL-13; a pan-matrix metalloproteinase (MMP) inhibitor (GM6001); specific inhibitors to MMP-1, -2, -3, and -8; and combinations of IL-13 with MMP inhibitors in separate conditions in serum-free media for 48 hours. Elastin (ELN) expression as well as MMP secretion and activity were quantified. Results of this study show that elastic fiber staining of airway biopsy tissue was significantly associated with methacholine PC 20 (i.e., the provocative concentration of methacholine resulting in a 20% fall in FEV 1 levels) in patients with asthma. IL-13 significantly suppressed ELN expression in asthmatic airway fibroblasts as compared with normal control fibroblasts. The effect of IL-13 on ELN expression was significantly correlated with postbronchodilator FEV 1 /FVC in patients with asthma. MMP inhibition significantly stimulated ELN expression in patients with asthma as compared with normal control subjects. Specific inhibition of MMP-1 and MMP-2, but not MMP-3 or MMP-8, reversed the IL-13-induced suppression of ELN expression. In asthma, MMP-1 and MMP-2 mediate IL-13-induced suppression of ELN expression in airway fibroblasts.
We found no significant impact on identification rate or number of SLN excised with the use of delayed versus immediate imaging. These findings support abandoning delayed lymphoscintographic imaging, except in those cases where aberrant drainage is suspected.
Pulmonary fibrosis (PF), a devastating disease affecting >105 Americans, can have environmental, autoimmune, or idiopathic causes. In lung, pulmonary neuroendocrine cells secrete GRP in response to oxidant exposures. Previously, we showed early GRP elevation precedes PF in hyperoxic baboons. Also, GRP blockade given to mice twice weekly abrogates radiation (RT)‐induced pulmonary fibrosis at 20 wks. We have now tested the hypothesis that early GRP secretion mediates PF by using a C57L/J mouse model of RT‐induced PF, with prolonged, irreversible kinetics like human PF. 1‐24h post‐RT mice were injected IP with PBS, 2A11 (GRP‐blocking mAb), or 77427 (GRP‐blocking small molecule). Sham controls were not irradiated. Urine was collected every 6h for 24h pre‐ and post‐RT. Lung tissue sections 10‐15 weeks post‐RT were stained for collagen (Masson's trichrome), elastin (Hall's method), and α‐smooth muscle actin immunostaining (SMA, myofibroblast marker). Quantitative image analysis was performed on alveolar photomicrographs by blinded observers. Mice had tenfold‐elevated urine GRP levels 0‐6h post‐RT, which declined to 2‐fold elevated at 18‐24h, abrogated by GRP blockade 1h post‐RT. Multiplex analysis of lungs at 24h showed only IL‐10 elevation, prevented by GRP blockade 1h post‐RT. One dose of GRP blockade 24h post‐RT abolished parameters of PF 15‐wks later: increased interstitial collagen, elastin, and myofibroblasts. In conclusion, urine GRP is elevated before 24h post‐RT, prevented by GRP blockade, which also blocks pathological hallmarks of PF months later. GRP is a novel biomarker for PF and GRP blockade might prevent PF and its sequelae.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.