PubMed · 11177113
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P Roy-Byrne, M B Stein. 2001. Inspiring panic.. https://doi.org/10.1001/archpsyc.58.2.123
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Surfactant protein D (SP-D) is a molecule of the innate immune system that recognizes the patterns of surface carbohydrate on pathogens and targets them for phagocytosis and killing. SP-D-deficient mice show an increased number of macrophages in the alveolar space, excess surfactant phospholipid, overproduction of reactive oxygen species, and the development of emphysema. We report here that SP-D-deficient mice have a 5- to 10-fold increase in the number of apoptotic and necrotic alveolar macrophages, as defined by annexin V and propidium iodine staining, respectively. Intrapulmonary administration of a truncated 60-kDa fragment of human recombinant SP-D reduces the number of apoptotic and necrotic alveolar macrophages and partially corrects the lipid accumulation in SP-D-deficient mice. The same SP-D fragment binds preferentially to apoptotic and necrotic alveolar macrophages in vitro, suggesting that SP-D contributes to immune homeostasis in the lung by recognizing and promoting removal of necrotic and apoptotic cells.
Elemental mercury (Hg(0)) is a ubiquitous toxic pollutant. Exposure to Hg(0) vapor typically is by inhalation, and the kidney is the primary target organ. Glutathione (GSH) and metallothionein (MT) appear to mitigate mercury toxicity. However, little is known about GSH or MT regulation after Hg(0) vapor exposure, particularly during pregnancy, a time of high sensitivity to most metals. Thus, this study sought to determine renal mercury accumulation and MT- and GSH-related gene expression following Hg(0) vapor exposure in nonpregnant, pregnant, and neonatal rats exposed in utero. Groups (n = 5) of pregnant rats (Long-Evans) were exposed to Hg(0) vapor (4 mg/m(3)) or air (control) for 2 h/d from gestational day (GD) 6 to 15, and kidneys from dams and pups were removed at various times during and after the onset of exposure. For comparative purposes, nonpregnant female rats were exposed to Hg(0) for 10 d under the same conditions. Renal mercury, MT protein, and GST activity were assayed by standard analytical techniques. Western blot analysis was also performed using antibodies against MT and GST-pi. GSH-related gene expression was studied by cDNA microarray. Hg(0) vapor exposure produced renal accumulation of mercury in nonpregnant, pregnant, and neonatal rats. However, the transplacentally exposed neonates accumulated approximately 1000-fold less mercury than adults. Hg(0) vapor exposure produced a time-dependent increase in renal MT protein in nonpregnant and pregnant rats, but not in neonatal rats. Maximum MT increases were observed on d 10 (fivefold) in nonpregnant and GD 15 (threefold) in pregnant rats. Activation of the MT gene by Hg(0) was confirmed at the translational level by Western blot analysis and at the transcriptional level by Northern blot analysis. Microarray analysis revealed a significant upregulation in the renal expression of the GST-pi, GST-Ya, and microsomal GST and GST5-5 genes in nonpregnant and pregnant rats. Western blot and enzyme assay confirmed the upregulation of GST genes after Hg(0) exposure. Thus, in response to Hg(0) vapor exposure, the expression of the MT gene and various GST genes is activated in nonpregnant and pregnant rats. Activation of these genes could be part of a defensive response directed at decreasing renal mercury toxicity, and may help divert the metal away from the fetus.
Trimellitic anhydride (TMA) causes asthma after a latency period of sensitization. In non-sensitized humans and animals, limited studies indicate that TMA exposure may also cause symptoms of asthma without a latency period. Our previous studies (J. Pharmacol. Exp. Ther. 296 (2001) 284) in a guinea pig model of TMA-induced asthma demonstrated that sensitization and the complement system were required for eosinophilia. TMA conjugated to guinea pig serum albumin (TMA-GPSA) was used to elicit the response. Since occupational exposure to TMA occurs by inhalation of dust, the present studies determined if exposure to TMA dust in a non-sensitized guinea pig elicited airway obstruction and inflammation, and whether a significantly greater response occurred after a latency period of sensitization. Guinea pigs were intradermally injected with either corn oil (non-sensitized animals) or 30% TMA (sensitized animals). Three weeks later they were challenged by intratracheal insufflation with 1 mg TMA dust or lactose dust (control) using a dry powder delivery device. Pulmonary resistance, dynamic lung compliance, mean arterial blood pressure and heart rate were monitored for 10 min. In non-sensitized guinea pigs, significant increases in pulmonary resistance and decreases in dynamic lung compliance and blood pressure occurred after TMA challenge. In sensitized animals, the same dose of TMA caused significantly greater effects compared to non-sensitized animals. In a separate experiment, cellular infiltration into the lung was determined 24 h after challenge with TMA dust or lactose dust. In both non-sensitized and sensitized animals, eosinophils in the lung tissue were increased after TMA dust challenge compared to controls. Thus, these studies suggest that the response in non-sensitized animals differs depending on whether TMA dust or TMA-GPSA is used to elicit the response. TMA dust elicits significant airway obstruction and eosinophilia in a non-sensitized animal, with even greater airway obstruction occurring in a sensitized animal.