Remodeling

Not all inflammatory responses to allergen are closely associated with Th2 pathways. Terada and colleagues measured increases in the acute inflammatory response element, thrombin, in the airways of subjects with asthma after segmental allergen challenge. This was accompanied by increases in fibronectin and TGF-ß. Furthermore, highly diluted lavage fluid was able to enhance fibroblast proliferation, and that effect was blocked by a specific inhibitor of thrombin. These studies suggest that some of the remodeling events occurring in allergic asthma may occur through thrombin-related pathways.

Some researchers think that thickening of the airway wall causes airway hyperresponsiveness and others think it protects against airway narrowing. In 45 patients with stable asthma (23 of whom were receiving inhaled glucocorticoids), Niimi and coworkers obtained helical computed tomography and a methacholine dose–response curve; sputum was also induced in a subgroup of 30 patients (16 of whom were receiving inhaled glucocorticoids). Airway sensitivity on methacholine testing was positively correlated with the eosinophil count (induced sputum), both in patients receiving glucocorticoids (r = 0.57) and in patients not receiving glucocorticoids (r = 0.49), but not with airway wall thickness. Airway reactivity on methacholine testing was negatively correlated with airway wall thickness, both in patients receiving glucocorticoids (r = -0.56) and in patients not receiving glucocorticoids (r = -0.55), but not with sputum eosinophil count. The authors conclude that thickening of the airway wall attenuates airway reactivity in patients with asthma. An editorial commentary by Pare accompanies this article.

Remodeling of the airway wall occurs in adult patients with asthma and thickening of the reticular basement membrane is pathognomonic of asthma. Payne and coworkers asked, "Do children with asthma display thickening of the reticular basement membrane?". They studied endobronchial biopsies from 19 children with difficult asthma, 10 children without asthma, 10 adults with mild asthma, 6 adults who had been intubated for life-threatening asthma, and 8 healthy adults. Thickness of the reticular basement membrane in children with asthma (median, 8.2 µm) was similar to that in adults with mild asthma (8.1 µm) and adults with life-threatening asthma (7.2 µm), and thicker than that in healthy children (4.4 µm) or healthy adults (4.9 µm). The authors conclude that thickening of the reticular basement membrane in children with difficult asthma is similar to that found in adults with asthma.

To determine whether inhaled glucocorticoid alters the vascular component of airway remodeling, Chetta and coworkers did a randomized, double-blind, parallel-group study of low-dose (100 µg twice daily) and high-dose (500 µg twice daily) fluticasone propionate in 30 patients with mild-to-moderate asthma. At baseline, bronchial biopsies revealed an increase in the number of vessels and vascular area in patients with asthma as compared with eight healthy subjects. In patients with asthma, the number of vessels correlated with vascular area (r = 0.58) and with the number of mast cells (r = 0.67). Both low- and high-dose fluticasone propionate decreased symptoms, bronchial responsiveness to methacholine, and inflammatory cells. Only the high dose of fluticasone propionate caused a decrease in the number of vessels, the vascular area, and thickness of the basement membrane. The authors conclude that a high dose of fluticasone propionate (500 µg twice daily) over 6 weeks alters airway remodeling consequent to a decrease in submucosal vascularity and thickness of the basement membrane.

Studies of hypervascularity of the bronchial wall in the airway remodeling of asthma have been confined to biopsy specimens. To investigate subepithelial vessels in a less invasive manner, Tanaka and coworkers used a novel, high-magnification bronchovideoscope in 24 patients with stable asthma, 13 patients with COPD, and 12 healthy control subjects. In patients with asthma, the redness of the bronchial mucosa seen on conventional bronchoscopy was found to be caused by a fine vascular network. The density of subepithelial vessels, in terms of both area and length, was greater in patients with asthma than in patients with COPD or the healthy subjects. The increase in subepithelial vessels was equivalent in 8 steroid-naive and 16 patients with asthma receiving inhaled glucocorticoids. The authors conclude that patients with asthma have increased subepithelial microvessels in the tracheal mucosa and these vessels are present even in newly diagnosed patients.

Transforming growth factor-ß is implicated in the remodeling of asthma: levels are increased in bronchial fluid, gene expression is increased in bronchial tissue, and the growth factor increases the release of collagen from airway smooth muscle. Burgess and coworkers examined whether transforming growth factor-ß induces expression and release of connective tissue growth factor in smooth muscle cells of the human airway. Transforming growth factor-ß induced both messenger RNA (38-fold increase at 24 hours versus 14-fold increase at time zero) and protein production (68-fold versus 4-fold increase) for connective tissue growth factor. The response was greater in airway smooth muscle cultured from patients with asthma than in airway smooth muscle from subjects without asthma. The authors conclude that messenger RNA and protein of connective tissue growth factor are found in smooth muscle cells of the human airway and that transforming growth factor-ß enhances gene expression for this growth factor in smooth muscle cells of patients with asthma.

Mechanical distortion of blood vessels is known to activate endothelial cells. To determine whether airway distension with the application of PEEP promotes leukocyte recruitment, Lim and Wagner used intravital microscopy in rat tracheas. Normal mechanical ventilation produced no change in leukocyte rolling velocity and the number of adherent cells over 2 hours. Ventilation with PEEP of 8 cm H₂O for 1 hour caused a decrease in leukocyte rolling velocity and an increase in adhesion. PEEP did not alter leukocyte recruitment in the mesenteric circulation. Application of PEEP distal to the site of measurement in the airway did not induce leukocyte recruitment. Pretreatment with endothelin receptor and selectin inhibitors blocks the effect of PEEP on leukocyte recruitment. The authors conclude that airway distension induced by PEEP leads to inflammatory leukocyte trafficking in the airways. An editorial commentary by Uhlig accompanies this article.

Citations 1-10 of 10 total displayed.

Immunostimulatory Oligonucleotides Attenuate Airways Remodeling in Allergic Monkeys

Michelle V. Fanucchi, Edward S. Schelegle, Gregory L. Baker, Michael J. Evans, Ruth J. McDonald, Laurel J. Gershwin, Eyal Raz, Dallas M. Hyde, Charles G. Plopper, and Lisa A. Miller
Am. J. Respir. Crit. Care Med. 170: 1153 -1157. First published online as doi:10.1164/rccm.200404-533OC [Abstract] [Full text]  

Increased Thrombin Activity after Allergen Challenge: A Potential Link to Airway Remodeling?

Masaki Terada, Elizabeth A. B. Kelly, and Nizar N. Jarjour
Am. J. Respir. Crit. Care Med. 169: 373 -377. First published online as doi:10.1164/rccm.200308-1156OC [Abstract] [Full text]  

Increased Airway Vascularity in Newly Diagnosed Asthma Using a High-magnification Bronchovideoscope

Hiroshi Tanaka, Gen Yamada, Toyohiro Saikai, Midori Hashimoto, Shintaro Tanaka, Kazuhiko Suzuki, Masaru Fujii, Hiroki Takahashi, and Shosaku Abe
Am. J. Respir. Crit. Care Med. 168: 1495 -1499. First published online as doi:10.1164/rccm.200306-727OC [Abstract] [Full text]  

Taking a Peep at the Upper Airways

Stefan Uhlig
Am. J. Respir. Crit. Care Med. 168: 1026-1027. [Full text]  

Airway Distension Promotes Leukocyte Recruitment in Rat Tracheal Circulation

Lina H. K. Lim and Elizabeth M. Wagner
Am. J. Respir. Crit. Care Med. 168: 1068 -1074. First published online as doi:10.1164/rccm.200207-690OC [Abstract] [Full text]  

Airway Hyperresponsiveness in Asthma: Geometry Is Not Everything!

Peter D. Paré
Am. J. Respir. Crit. Care Med. 168: 913-914. [Full text]  

Relationship of Airway Wall Thickness to Airway Sensitivity and Airway Reactivity in Asthma

Akio Niimi, Hisako Matsumoto, Masaya Takemura, Tetsuya Ueda, Kazuo Chin, and Michiaki Mishima
Am. J. Respir. Crit. Care Med. 168: 983 -988. First published online as doi:10.1164/rccm.200211-1268OC [Abstract] [Full text]  

Vascular Component of Airway Remodeling in Asthma Is Reduced by High Dose of Fluticasone

Alfredo Chetta, Andrea Zanini, Antonio Foresi, Mario Del Donno, Antonio Castagnaro, Raffaele D'Ippolito, Simonetta Baraldo, Renato Testi, Marina Saetta, and Dario Olivieri
Am. J. Respir. Crit. Care Med. 167: 751 -757. First published online as doi:10.1164/rccm.200207-710OC [Abstract] [Full text]  

Expression of Connective Tissue Growth Factor in Asthmatic Airway Smooth Muscle Cells

Janette K. Burgess, Peter R. A. Johnson, Qi Ge, Wendy W. Au, Maree H. Poniris, Brent E. McParland, Greg King, Michael Roth, and Judith L. Black
Am. J. Respir. Crit. Care Med. 167: 71-77. [Abstract] [Full text]  

Early Thickening of the Reticular Basement Membrane in Children with Difficult Asthma

Donald N. R. Payne, Andrew V. Rogers, Ellinor Ädelroth, Venkata Bandi, Kalpalatha K. Guntupalli, Andrew Bush, and Peter K. Jeffery
Am. J. Respir. Crit. Care Med. 167: 78-82. [Abstract] [Full text]