Stem cell factor-induced airway hyperreactivity in allergic and normal mice

Abstract

The induction of airway hyperreactivity during allergic responses involves multiple ill-defined mechanisms. Recently a role for stem cell factor (SCF) in the development of allergic eosinophilic airway inflammation has been identified. In the present study we demonstrate that SCF has a role in both the inflammatory response and airway hyperreactivity. Neutralization of SCF or examination of SCF-mutant mice, which were deficient in SCF and pulmonary mast cells, demonstrated significant alterations in the allergen-induced airway hyperreactive responses. The reduced hyperreactivity response was accompanied by a significant reduction in eosinophil accumulation. To examine the direct role of SCF on airway hyperreactivity, we administered SCF into the airways of normal mice via intratracheal injections and demonstrated a dose dependent increase in airway hyperreactivity at 4 hours that was maintained at 24 hours after administration. Instillation of SCF into SCF-deficient (mast cell deficient) mice demonstrated significantly lower increases in airway hyperreactivity compared with the littermate controls with normal mast cell numbers. These studies demonstrate that locally expressed SCF can induce changes in airway physiology via mast cell activation, verifying the role of SCF in allergic airway inflammation and hyperreactivity.

Figures

Figure 1.

Neutralization of SCF during allergic airway inflammation attenuates airway hyperreactivity. Sensitized animals were rechallenged with allergen containing purified 0.5 mg polyclonal IgG anti-SCF or control antibody via an intratracheal instillation. At 24 hours after allergen, challenge animals were assessed for the presence of airway hyperreactive responses after a challenge of an optimal dose of methacholine (100 μg/kg). Data represent mean ± SE of 8 to 10 animals/group. *P < 0.05

Figure 2.

Neutralization of SCF decreases peribronchial eosinophil accumulation during allergic airway responses. Histological sections from the lungs of allergic mice were examined for peribronchial eosinophil accumulation after treatment with anti-SCF or control antibody during an allergic airway response. Eosinophils were enumerated in 100 high-power fields from multiple tissue sections of each mouse. Data represent the mean ± SE from 8 to 10 mice/group. *P < 0.05

Figure 3.

SCF-deficient mice (Sl/Sld) have decreased eosinophil accumulation within their airways. Allergen-sensitized littermate or SCF-deficient mice were challenged intratracheally with allergen, and BAL fluid samples were taken and percent of eosinophils determined via differential staining on cytospin-fixed slides. Data represent mean ± SE of six mice/group. *P < 0.05

Figure 4.

SCF-mutant mice have decreased airway hyperreactivity responses. Allergen-sensitized littermate or SCF-deficient mice were challenged intratracheally with allergen and assessed for airway hyperreactivity responses to an optimal dose of methacholine (100 μg/kg). Data represent change in resistance in six mice/group. *P < 0.05

Figure 5.

Instillation of SCF induces airway hyperreactivity. Increasing doses of SCF were intratracheally instilled into the lungs of normal, unsensitized mice. After 4 hours the mice were assessed for increased airway hyperreactivity responses. Data represent mean ± SE of four to six mice/group. *P < 0.05.

Figure 6.

Time course of SCF-induced airway hyperreactivity in normal mice. SCF (50 ng/ml) was intratrachally instilled into normal, unsensitized mice, and airway hyperreactivity was assessed at various time points after treatment. The data represent four to six mice/group. *P < 0.05.

Figure 7.

Instillation of SCF into SCF-mutant mice does not induce an airway hyperreactive response. SCF (50 ng/ml) was intratrachally instilled into normal, unsensitized littermate control, and SCF-mutant mice and airway hyperreactivity was assessed at various time points after treatment. Vehicle control mice demonstrated a change in resistance to methacholine of 0.7 ± 0.2, a similar response as the SCF-mutant mice instilled with SCF. The data represent five mice in each group. *P < 0.05