Mast cells play a key role in the developmentof late airway hyperresponsiveness through TNF‐αin a murine model of asthma

Abstract

We have investigated the role of TNF‐α in mast cell‐mediated late airway hyperresponsiveness (AHR) using mast cell‐deficient WBB6F1‐W/Wv (W/Wv) mice in a murine model of asthma, which exhibits a biphasic increase in AHR. TNF‐α levels in the airway and magnitude of late AHR in response to airway allergen challenge were severely impaired in W/Wv mice compared to their littermates. In addition to TNF‐α, cytosolic phospholipase A2 (cPLA2) phosphorylation and enzymatic activity in the lungs were also impaired in W/Wv mice. Either anti‐TNF‐α antibody or an inhibitor of cPLA2 abolished late AHR in congeneic +/+ mice. Intratracheal administration of TNF‐α resulted in increases in late AHR, cPLA2 phosphorylation, cPLA2 activity, and phosphorylation of mitogen‐activated protein kinases. Mast cell replacement restored airway TNF‐α level, cPLA2 phosphorylation and enzymatic activity in the lungs as well as late AHR in W/Wv mice. These data indicate that mast cells play a key role in the development of late AHR through liberation of TNF‐α.

Mouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding bronchial responsiveness, inflammation, and cytokine production

“…This increased bronchial hyperresponsiveness to methacholine in BALB/c mice could also be explained by increased mast cell numbers found in the lung tissue of those mice since the degranulation of these cells induces a release of mediators such as histamine, leukotrienes, and TNF-α [22]. Those mediators markedly increase vascular permeability, followed by inflammatory cell recruitment, and further release of pro-inflammatory mediators, but they also act directly on smooth muscle cells and consequently increase bronchial hyperreactivity [23][24][25]. Mast cells are also a major source of IL-4, which is increased in those mice after allergen exposure [26].…”

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

“…Mast-cell-derived TNF contributes to airway hyperreactivity and inflammation in models of allergic airway inflammation 67,70,79 , probably in part due to its ability to promote T-cell recruitment 67,70 and to enhance local levels of IL-4, IL-5, IL-13 and IL-17 (Ref. 67 ).…”

Mast cells play a key role in Th2 cytokine-dependent asthma model through production of adhesion molecules by liberation of TNF-α

“…Suspended bone marrow cells from +/+ mice were cultured in WEHI-3 conditioned medium containing IL-3 for 4-5 weeks, at which time the cell populations were composed of ＞ 95% immature mast cells, as assessed by Louis, MO), as described previously, with some modifications (Williams and Galli, 2000;Kim et al, 2007) (Supplemental Data Figure S1). In brief, mice were immunized by intraperitoneal injection of 20 μg OVA and saline in a total volume of 200 μl on days 0 and 14.…”