Neutrophil and Eosinophil Granulocytes as Key Players in a Mouse Model of Chemical-Induced Asthma

Abstract

Diisocyanates are an important cause of chemical-induced occupational asthma. This type of immunologically mediated asthma is often characterized by a predominant granulocytic inflammation in the airways, rather than an infiltration by lymphocytes. We sought to determine the contribution of granulocytes in the outcome of chemical-induced asthma using general and specific leukocyte depletion strategies in an established mouse model of isocyanate asthma. On days 1 and 8, BALB/c mice received dermal applications with toluene-2,4-diisocyanate (TDI) or vehicle (acetone olive oil), followed by two ip injections of cyclophosphamide (CP, days 11 and 13), or one iv injection of antigranulocyte receptor 1 (aGR1, day 13) monoclonal antibody (mAb), or two ip injections of Ly6G-specific mAb (1A8, days 13 and 14). On day 15, the mice were challenged (oropharyngeal administration) with TDI or vehicle. The next day, we assessed methacholine airway hyperreactivity (AHR); bronchoalveolar lavage differential cell count; histopathology and total serum IgE; and auricular lymphocyte subpopulations and release of interleukin (IL)-2, IL-4, IL-10, IL-13, and gamma interferon by these lymphocytes. CP depleted all leukocyte types and completely prevented AHR and airway inflammation. aGR1 depleted granulocytes and CD8(+) lymphocytes, which resulted in a partial prevention in AHR but no decrease in airway inflammation. Depletion of Ly6G-positive granulocytes, i.e., both neutrophils and eosinophils, prevented AHR and lung epithelial damage and significantly reduced airway inflammation. Injection of aGR1 or 1A8 led to significantly changed cytokine release patterns in TDI-treated mice. Granulocytes, both neutrophils and eosinophils, are key cellular players in this model of chemical-induced asthma.

The enigmatic role of the neutrophil in asthma: Friend, foe or indifferent?

“…Despite the clear indication that neutrophils can be a prominent 100 Additionally, in a mouse model of chemical induced asthma, it was demonstrated that neutrophil depletion prevented airway hyperresponsiveness (AHR), lung epithelial damage and reduced airway inflammation. 101 Studies in dogs have also supported the notion that neutrophils may contribute to the pathology of asthma, with ozone-induced AHR associated with increased numbers of intraepithelial neutrophils 102 and the depletion of neutrophils reducing AHR in this model. 103 IL-17 is a cytokine that is consistently linked with asthma and particularly the severe forms of the disease, 104,105 with several studies reporting correlations between IL-17 levels and the number or neutrophils retrieved from sputum, BAL and blood.…”

“…A PATHOLOGICAL ROLE FOR NEUTROPHILS IN ASTHMA? Additionally, in a mouse model of chemical induced asthma, it was demonstrated that neutrophil depletion prevented airway hyperresponsiveness (AHR), lung epithelial damage and reduced airway inflammation 101. Nonetheless, the general consensus is that neutrophils are detrimental and indicate a worse prognosis: neutrophilic inflammation in the asthmatic lung is generally associated with enhanced severity of disease, diminished responsiveness to corticosteroids, lower lung function and is a feature of rapid onset asthmatic deaths.…”

Anti‐inflammatory effects of the GAG‐binding CXCL9(74‐103) peptide in dinitrofluorobenzene‐induced contact hypersensitivity in mice

“…33,36,37,55 It seems that neutrophils, attracted by mast cell-derived mediators, are required for the activation and migration of dendritic cells (DCs) and the subsequent priming of T cells in the lymph nodes. 33,36,37,55 It seems that neutrophils, attracted by mast cell-derived mediators, are required for the activation and migration of dendritic cells (DCs) and the subsequent priming of T cells in the lymph nodes.…”

Comparable Function of γ-Tocopherols in Asthma Remission by Affecting Eotaxin and IL-4

“…Bronchial asthma is a chronic inflammatory disorder of the airways in which many cells, particularly eosinophils, may play important roles through the release of various mediators [16][17][18]. There is strong evidence that an imbalance between the reducing and oxidizing systems favoring a more oxidative state is present in the airway inflammation and a deficiency in the amount of antioxidants exists in the asthmatic airway [19,20].…”