Abstract
Crystals seldom form spontaneously within tissues of mammals, except in the urinary tract or in association with eosinophil-rich diseases in humans (Charcot-Leyden crystals). Endogenously formed eosinophilic crystals have been reported in respiratory tract and other tissues of several strains of mice, but the biochemical characterization of these crystals has not been reported. In this study, eosinophilic crystal formation was examined in homozygous C57BL/6J viable motheaten mice, lung-specific surfactant apoprotein C promoter/soluble human tumor necrosis factor p75 receptor type II fusion protein transgenic mice (C57BL/6NTac x Sv/129), and CD40L-deficient mice with spontaneous Pneumocystis carinii infection. In viable motheaten but not wild type mice, rapidly developing crystals represented a major feature of the fatal lung injury induced by macrophage dysregulation. Conversely, eosinophilic crystals did not form until 4-8 months of age in transgenic and CD40L-deficient mice and were present in 10-30% of age-matched wild type controls. Mass spectrometry analysis of proteins from bronchoalveolar lavage fluid identified the crystals as Ym1, sometimes referred to as T-lymphocyte-derived eosinophil chemotactic factor. The Ym1 sequence was homologous to chitinase, and enzymatic assays indicated a 3-5-fold increase in chitinase activity compared with control mice. Intracellular and extracellular crystals associated with epithelial damage suggested that the crystals may contribute to lung inflammation through mechanical damage and enzymatic degradation.
Highlights
As early as 1905 [1], eosinophilic crystals were reported microscopically in the respiratory tract, the biliary tree, and other tissues of C57BL/6, Swiss Webster, and related strains of mice [2,3,4,5,6,7]
Tissue Characterization of Eosinophilic Crystals—Eosinophilic crystals were identified in varying numbers, sizes, and shapes within the cytoplasm of alveolar macrophages and multinucleate giant cells and free within alveolar spaces in the lungs of mev/mev (Fig. 1A), SPCTNFRIIFc transgenic (Fig. 1B) and wild type litter mate control mice, CD40L-deficient mice (Fig. 1C), and occasionally in older C57BL/6 control mice
Except for P. carinii in CD40L-deficient mice, all mice were determined to be free of other spontaneous murine pathogens or other confounding diseases that might alter the frequency of pulmonary damage and eosinophilic crystal formation
Summary
Mice—The C57BL/6J viable motheaten mice were initially obtained from Jackson Laboratories (Bar Harbor, ME) and propagated by heterozygous mating. Control animals included ϩ/ϩ and mev/ϩ littermates, and sex- and age-matched C57BL/6NTac or BALB/c mice (Taconic, Germantown, NY). The SPCTNFRIIFc transgenic mice (C57BL/ 6NTac ϫ Sv/129) secrete soluble human tumor necrosis factor receptor p75 under the control of the surfactant apoprotein C promotor [17] and were paired with littermates or age-matched control mice
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