Impairment of Endotoxin-Induced Macrophage Inflammatory Protein 2 Gene Expression in Alveolar Macrophages in Streptozotocin-Induced Diabetes in Mice

Abstract

To elucidate the mechanism of the high incidence of lower respiratory tract infections in patients with diabetes mellitus, we investigated the kinetics of production of macrophage inflammatory protein 2 (MIP-2), an important mediator of lung neutrophil recruitment, using mice with streptozotocin-induced diabetes. Intratracheal challenge with 1 mg of lipopolysaccharide (LPS), an endotoxin, per kg of body weight resulted in a time-dependent increase in the levels of MIP-2 protein in bronchoalveolar lavage (BAL) fluid, with the peak concentration (49.4 ؎ 13 ng/ml) occurring at 3 h and significant neutrophil accumulation becoming apparent by 3 h in normal mice. In diabetic mice, the peak level of MIP-2 protein in BAL fluid did not occur until 6 h and was reduced to 21.9 ؎ 10 ng/ml. Immunohistochemical studies using anti-MIP-2 antibody confirmed that the main cellular source of MIP-2 in the lung after LPS challenge was alveolar macrophages (AMs) in normal mice. The lungs in diabetic mice, however, showed no AMs staining for MIP-2 within 3 h after LPS challenge. PCR analysis using whole-lung RNA showed a time-dependent increase in MIP-2 mRNA levels after LPS instillation. The level of MIP-2 mRNA in diabetic mice was markedly decreased compared to that in normal mice. Our results indicate that impairment of MIP-2 mRNA expression in the AMs in diabetic mice resulted in delayed neutrophil recruitment in the lungs, and this may explain the development and progression of pulmonary infection in diabetes mellitus.

Comparison Of Immunomodulator mRNA and Protein Expression in the Lungs ofStachybotrys chartarumSpore-Exposed Mice

“…The toxins sequestered in JS 58-17 spores include macrocyclic trichothecenes that are among the most potent protein synthesis inhibitors known because they bind to peptidyl transferase and inhibit peptide elongation (Riley & Norred, 1996;Sorenson et al, 1987). In mouse lungs, these toxins diffuse from spores into surrounding tissues and bind to the ribosomes of various lung cells, including alveolar macrophages (AMs) (Gregory et al, 2004), the predominant source for MIP-2 in the lung (Amano et al, 2000). It therefore seems reasonable to conclude that these toxins inhibit cytokine/chemokine transcript translation processes and depress immunomodulator expression.…”

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

“…29,76 Total RNA was extracted with the RNeasy Mini Kit (Qiagen, 74104) from mouse lung homogenates and from nasal brushing of CF patients.…”

Impaired inflammatory responses to multiple Toll-like receptor ligands in alveolar macrophages of streptozotocin-induced diabetic mice

“…Of the multiple resident macrophage populations, alveolar macrophages (AMs), highly specialized mononuclear phagocytes, are the first-line defense to invading pathogens and play a central role in innate respiratory host defense [17]. To date, only a small number of reports have addressed the functions of AMs, such as depressed respiratory burst [18], impaired phagocytic and bactericidal functions [19], impaired lipopolysaccharide (LPS)-induced macrophage inflammatory protein (MIP)-2 gene expression [20], decreased capacity of cytokine (tumor necrosis factor-alpha (TNF-a) and interleukin (IL)-12) secretion, and nitric oxide production in tuberculosis [21] in diabetic animal models. Unexpectedly, recent works concerning macrophage inflammatory response under hyperglycemic conditions or diabetes have been performed mainly on peritoneal [14-16, 22, 23] and bone marrow-derived macrophages (BMDMs) [24,25], whereas the data on AMs remain limited.…”