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Concentration of Cytokines and Growth Factors in BAL Fluid After Allergen Challenge in Asthmatics and Their Effect on α-Smooth Muscle Actin and Collagen III Synthesis by Human Lung Fibroblasts* FREE TO VIEW

Vikas Batra, MD; Sandhya Khurana, MD; Ali I. Musani, MD; Annette T. Hastie, PhD; Katherine A. Carpenter, BS; James G. Zangrilli, MD, FCCP; Stephen P. Peters, MD, PhD, FCCP
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From Thomas Jefferson University, Philadelphia, PA.

Correspondence to: Stephen P. Peters, MD, PhD, FCCP, Wake Forest University Health Sciences Center, Center for Human Genomics, Medical Center Blvd, Winston-Salem, NC 27157; e-mail: sppeters@wfubmc.edu

Chest. 2003;123(3_suppl):398S-399S. doi:10.1378/chest.123.3_suppl.398S
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Asthma is characterized histologically by bronchial subepithelial fibrosis and increased numbers of myofibroblasts. It has been proposed that these myofibroblasts are responsible for the characteristic subepithelial collagen deposition seen in asthma. We hypothesized that the concentration of growth factors and cytokines that is important in asthmatic airway remodeling are elevated in BAL fluid after segmental antigen challenge (SAC). We further hypothesized that these growth factors and cytokines increase α-smooth muscle actin (SMA) and collagen III synthesis by human lung fibroblasts (HLFs).

Transforming growth factor (TGF)-β1, TGF-β2, interleukin (IL)-4, and IL-13 concentrations were measured in BAL fluid concentrates from 10 asthmatic patients and 9 nonasthmatic control subjects before they underwent SAC and 1 day, 1 week, and 2 weeks after undergoing SAC. Five lines of HLF were stimulated by exogenous addition of TGF-β1, TGF-β2, IL-4, and IL-13 (range, 0.01 to 10 ng/mL) for 48 h. Harvested supernatants were analyzed for determination of collagen III levels. Cell lysates were tested for α-SMA by Western blot analysis.

Before SAC, there was no significant difference in the BAL fluid concentrations of TGF-β1, IL-4, and IL-13 between asthmatic patients and nonasthmatic subjects. However, TGF-β2 levels were higher in nonasthmatic subjects. In asthmatic patients, the BAL fluid concentration of these cytokines and growth factors increased significantly 1 day after undergoing SAC (p < 0.05). TGF-β1, TGF-β2, and IL-13 concentrations returned toward baseline by 1 week after SAC, whereas IL-4 levels remained elevated until 2 weeks after SAC. In nonasthmatic subjects there was no significant change in the concentrations of these cytokines and growth factors after undergoing SAC. On stimulus of HLF by exogenous addition of these growth factors and cytokines, TGF-β1 and IL-4 increased α-SMA levels in a dose-dependent manner (p < 0.05 for both). TGF-β2 also significantly increased α-SMA expression at concentrations of 1 and 10 ng/mL (p < 0.01). In contrast, increasing concentrations of IL-13 had no effect on α-SMA expression. The analysis of collagen III revealed that only IL-4 increased collagen III synthesis in a dose-dependent manner (p < 0.05). TGF-β2 increased collagen III synthesis at a concentration of 1 ng/mL. Increasing concentrations of TGF-β1, TGF-β2, and IL-13 caused no significant dose-dependent increase in collagen III synthesis

Our conclusions were as follows: (1) TGF-β1 or ΤGF-β2 stimulation leads to phenotypic change of fibroblasts to myofibroblasts, however, this does not correspond to a dose-dependent increase in collagen III synthesis; (2) IL-13 has no direct role in these features of airway remodeling; and (3) BAL fluid concentrations of IL-4 remain elevated for at least 2 weeks after antigen challenge in asthmatic patients. IL-4 causes dose-dependent increases in both α-SMA and collagen III synthesis. Therefore, IL-4 may be one of the important cytokines mediating airway remodeling in asthmatic patients.

Abbreviations: HLF = human lung fibroblast; IL = interleukin; SAC = segmental antigen challenge; SMA = smooth muscle actin; TGF = transforming growth factor

This research was supported in part by National Institutes of Health grants AI24509 and HL67663.




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