Pulmonary neuroendocrine cells (PNECs) are airway epithelial cells that are capable of secreting a variety of neuropeptides. PNECs are scattered throughout the bronchial tree either as individual cells or clusters of cells termed neuroepithelial bodies (NEBs). PNECs and their secretory peptides have been considered to play a role in fetal lung development. Although the normal physiological function of PNECs and neuropeptides in normal adult lungs and in repair from lung injury is not known, PNEC hyperplasia has been associated with chronic lung diseases, such as bronchopulmonary dysplasia, and with chronic exposures, such as hypoxia, tobacco smoke, nitrosamines, and ozone. To evaluate changes in PNEC number and distribution after acute airway injury, FVB/n mice were treated with either naphthalene or vehicle. Naphthalene is an aromatic hydrocarbon that, at the dose used in this study, selectively destroys nonciliated bronchial epithelial cells (Clara cells) through cytochrome P-450-mediated metabolic activation into cytotoxic epoxides. PNECs were identified by immunohistochemical analysis of calcitonin gene-related peptide-like immunoreactivity (CGRP-IR). Proliferating cells were marked with [(3)H]thymidine incorporation. Acute naphthalene toxicity results in PNEC hyperplasia that is detectable after 5 days of recovery. PNEC hyperplasia is characterized by increased numbers of NEBs without significant changes in the number of isolated PNECs and by increased [(3)H]thymidine labeling of CGRP-IR cells. These data show that cell proliferation contributes to PNEC hyperplasia after acute airway injury and suggest that PNECs may be capable of more rapidly increasing their number in response to injury than previously recognized.

Whole-mount airway preparations isolated from the lungs of mice treated by intraperitoneal injection of naphthalene and allowed to recover for 5 days were examined for the distribution and abundance of solitary pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) along the main axial pathway of the right middle lobe. Sham mice treated with corn oil vehicle were examined in a similar manner. An antibody to calcitonin gene-related peptide, a neuroendocrine cell marker, was used to identify the location, size, and number of PNECs and NEBs in the airways. After naphthalene treatment and epithelial repair, NEBs were significantly increased along the walls of the airways as well as on branch point ridges. The surface area covered by NEBs composed of 20 or fewer PNECs was significantly enlarged after naphthalene treatment compared with control NEBs of an equivalent cell number. The PNEC number per square millimeter was also increased more than threefold above control values after naphthalene treatment. These findings provide further support for a key role of neuroendocrine cells in the reparative process of airway epithelial cell renewal after injury.

Silver nanoparticles (Ag NPs) can be found in myriad consumer products, medical equipment/supplies, and public spaces. However, questions remain regarding the risks associated with Ag NP exposure. As part of a consortium-based effort to better understand these nanomaterials, this study examined how Ag NPs with varying sizes and coatings affect pulmonary responses at different time-points. Four types of Ag NPs were tested: 20 nm (C20) and 110 nm (C110) citrate-stabilized NPs, and 20 nm (P20) and 110 nm (P110) PVP-stabilized NPs. Male, Sprague Dawley rats were intratracheally instilled with Ag NPs (0, 0.1, 0.5, or 1.0 mg/kg bodyweight [BW]), and bronchoalveolar lavage fluid (BALF) and lung tissues were obtained at 1, 7, and 21 days post-exposure for analysis of BAL cells and histopathology. All Ag NP types produced significantly elevated polymorphonuclear cells (PMNs) in BALF on Days 1, 7, and/or 21 at the 0.5 and/or 1.0 mg/kg BW dose(s). Histology of animals exposed to 1.0 mg/kg BW Ag NPs showed patchy, focal, centriacinar inflammation for all time-points; though neutrophils, macrophages, and/or monocytes were also found in the airway submucosa and perivascular regions at Days 1 and 7. Confocal microscopy of ethidium homodimer-stained lungs at Day 1 showed dead/dying cells at branch points along the main airway. By Day 21, only animals exposed to the high dose of C110 or P110 exhibited significant BALF neutrophilia and marked cellular debris in alveolar airspaces. Findings suggest that 110 nm Ag NPs may produce lasting effects past Day 21 post instillation.

Exposure to environmental tobacco smoke (ETS) has been shown to increase allergic sensitization and reactivity and there has been some suggestion that the influence of ETS on the allergic response is dissimilar in males and females. It is to be determined whether gender differences exist in the IgE response to ovalbumin (OVA) sensitization following ETS exposure from the neonatal period through adulthood. To address this thesis, we examined gender differences in OVA sensitization of BALB/c mice housed from birth through adulthood under smoking and nonsmoking conditions. At 6 weeks of age (day 0) all mice were injected i.p. with OVA in aluminum hydroxide adjuvant followed by three 20 min exposures to 1% aerosolized OVA between day 14 and 80. There were significantly (p<0.05) more total and OVA specific IgE and IgG1 in the serum of females compared to males. Moreover, these sex responses, along with eosinophilia, were further enhanced in mice exposed to ETS. There were also significantly more IgE positive cells in the lungs of female, but not male, mice exposed to ETS compared with ambient air (p<0.05). There was also an elevation of Th2 cytokines (IL4, IL5, IL10, and IL13) after re-stimulation of lung homogenates following ETS exposure. These data demonstrate that female animals are significantly more susceptible than males to the influence of ETS on the allergic response.

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