Tumor Necrosis Factor Plays an Essential Role in Determining Hypersensitivity Pneumonitis in a Mouse Model

Abstract

We examined the importance of the cytokine tumor necrosis factor-alpha (TNF-alpha) in a mouse model of hypersensitivity pneumonitis (HP). Mice of the C57BL/6 strain were instilled intranasally 3 days/wk for 3 wk with 150 micrograms of the actinomycete Faenia rectivirgula (Micropolyspora faeni) to induce HP as a model of farmer's lung. This experimental model was associated with a progressive inflammation in the lungs of challenged mice, seen histologically as cellular infiltrates of large quantities of macrophages and lymphocytes and some neutrophils. The disease in challenged mice treated with a control rabbit serum was also associated with a substantial release of tumor TNF-alpha (up to 80 U/ml of TNF-alpha in the bronchoalveolar lavage [BAL] at 3 wk after beginning of treatment) and interleukin-1, which peaked at 1 wk (approximately 300 U/ml) and diminished thereafter. A very large increase in BAL cell number (11-fold increase versus saline controls) and an enhanced release potential for TNF-alpha by alveolar macrophages was also seen. Lung fibrosis was also evident in challenged animals, as demonstrated by a 2-fold increase in hydroxyproline levels. Infusion of challenged mice with a rabbit polyclonal antibody against TNF-alpha (2 mg/wk) completely abrogated the disease, as mice so treated had normal lung histology. Anti-TNF-alpha blocked cellular recruitment in the lungs (only a 2-fold increase at week 3); it also completely abolished TNF-alpha secretion in the BAL and drastically reduced interleukin-1 levels in this fluid. Anti-TNF-alpha also abolished lung index increases and lung fibrosis, with both parameters similar to that of saline-instilled mice.(ABSTRACT TRUNCATED AT 250 WORDS)

IL-4-Secreting NKT Cells Prevent Hypersensitivity Pneumonitis by Suppressing IFN-γ-Producing Neutrophils

“…H ypersensitivity pneumonitis (HP) 3 represents a group of related inflammatory interstitial lung diseases caused by the repeated inhalation of and consequent sensitization to a wide variety of environmental organic dusts, fungi, and molds (1,2). The most common Ags are thermophilic actinomycetes, which cause farmer's lung disease (1).…”

“…Several immune cell types, including neutrophils, lymphocytes, monocytes and macrophages, are involved in the development of HP (1,2). After Ag exposure, the number of alveolar macrophages is increased, and these cells secrete cytokines and chemokines such as TNF-␣, IL-1, IL-8, and MIP-1␣, which attract neutrophils and lymphocytes (3)(4)(5). IL-8 acts as a chemotactic factor for neutrophils and T cells, and its levels in bronchoalveolar lavage fluid (BALF) from patients with HP are correlated with the number of neutrophils and response to treatment (4).…”

IFN-γ production by innate immune cells is sufficient for development of hypersensitivity pneumonitis

“…Farmers Lung Disease is one of the most common types of HP and is caused by repeated inhalation of Saccharopolyspora rectivirgula (SR), which is commonly found in moldy hay [2]. One of the animal models used to study HP is the well-characterized SR model [3,4]. Mice intranasally inoculated with SR for 3 days/week for 3 weeks develop an alveolitis that is initially neutrophilic but becomes more lymphocytic in the days following exposure.…”

Chemokine production during hypersensitivity pneumonitis

“…One of the animal models used to study HP is the wellcharacterized SR model [4][5][6][7]. Mice intranasally inoculated with SR for 3 days/week for 3 consecutive weeks develop lymphocytic alveolitis and granulomas similar to those found in humans.…”