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* From the National Jewish Medical and Research Center, Denver, CO.
Correspondence to: Monica Kraft, MD, FCCP, National Jewish Medical and Research Center, B-120, 1400 Jackson St, Denver, CO 80206; e-mail: kraftm{at}njc.org
Airway remodeling in asthma patients has received a great deal of attention as a process whereby significant structural abnormalities of the bronchial wall occur and may lead to a state of fixed, or irreversible, airway obstruction.1 Among these abnormalities, a thickening of the subepithelial basement membrane has been described repeatedly, and even has been shown in some studies to correlate with bronchial hyperresponsiveness.2 This morphologic change is thought to be due primarily to increased collagen deposition beneath the bronchial epithelium by airway fibroblasts.3
We4
have previously shown that dexamethasone (DX), interleukin (IL)-4, and IL-13 enhance the proliferation of proximal airway fibroblasts from patients with asthma. However, the proliferative and synthetic characteristics of distal lung fibroblasts in response to these mediators are unknown. In an ongoing study, six subjects with nocturnal worsening of asthma (mean [± SD] overnight fall in FEV1, 20.0 ± 2.7%) underwent bronchoscopy with transbronchial biopsy at 4:00 AM (mean FEV1, 69 ± 4% predicted). Biopsy specimens were placed in Dulbecco modified Eagle medium supplemented with fetal bovine serum (10%), streptomycin (100 µg/mL), penicillin (10,000 U/mL), and gentamicin (100 µg/mL), and were cultured until > 50% confluency was established (ie, approximately 8 to 20 days). Cells were passaged up to four times for data collection. Immunostaining with vimentin (Dako; Carpenteria, CA), Ab-1 (Calbiochem; San Diego, CA), and 
-smooth muscle actin (Dako) confirmed fibroblast identity. For determining fibroblast proliferation, freshly trypsinized cells were seeded in 96-well plates at 104 cells per well and were incubated with IL-4 (50 U/mL), IL-13 (10 ng/mL), and a combination of the two for 48 h in the presence and absence of DX (concentration range, 10-6 through 10-10 mol/L). Proliferation was determined via [3H]thymidine incorporation, and procollagen I production was determined using a sandwich enzyme-linked immunosorbent assay.
DX alone, at concentrations ranging from 10-8 to 10-10 mol/L, significantly increased fibroblast proliferation from baseline values, with mean induction responses of 1.8 ± 0.3-fold (p = 0.03), 1.6 ± 0.2-fold (p = 0.007), and 1.5 ± 0.1-fold (p = 0.005), respectively. However, the most pronounced proliferative response observed was that arising from the combination of IL-4, IL-13, and DX (concentration range, 10-6 to 10-8 mol/L). The increase in proliferation from baseline values ranged from 2.6-fold to 2.8-fold (p < 0.0035 [comparison to unstimulated control subjects for DX at concentrations ranging from 10-6 to10-8 mol/L]). DX at concentrations ranging from 10-6 to 10-9 mol/L significantly decreased procollagen production (range of decrease, 1.5-fold to 2-fold; p = 0.014 to 0.02), but IL-4 and IL-13, either alone or in combination with DX, had no effect on collagen production.
In conclusion, the cytokines that were critical to the asthma phenotype, IL-4 and IL-13, and corticosteroids enhanced the proliferation of distal lung fibroblasts.
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