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Clara cell secretory protein (CCSP) is a protective lung protein that is believed to have antioxidant, immunomodulatory, and anticarcinogenic properties; to be present in all adult mammals; and to be well conserved in rodents, humans, and nonhuman primates. The rationale for this study is to define the distribution and abundance of CCSP in the airway epithelium and lavage fluid of the adult rhesus monkey and to provide information for evaluating CCSP as a marker of Clara cells and as a biomarker of lung health. Lung tissue and lavage fluid from 3-yr-old rhesus monkeys were examined using histopathology and immunohistochemistry. Proximal bronchi, midlevel bronchi, and terminal/ respiratory bronchioles were compared for immunohistochemical localization of CCSP in three-dimensional whole mounts as well as in paraffin and Araldite sections. Immunoreactive CCSP was found in nonciliated cells throughout the airway epithelium. Proximal and midlevel airways had the highest labeling. CCSP decreased in distal airways, and respiratory bronchioles had little to no CCSP. CCSP in the most distal airways was in tall cuboidal cells adjacent to the pulmonary artery. Although a large number of cells were present in the terminal bronchioles that would be classified as Clara cells based on morphology (nonciliated cells with apical protrusions), only a small number stained positively for immunoreactive CCSP. Semiquantitative analysis of Western blots indicated that changes in lavage CCSP are consistent with, and may be predictive of, overall CCSP levels in the airway epithelium in this primate species that is phylogenetically similar to humans. Macaca mulatta; bronchial epithelium; lung; CC10; CC16; SCGB 1A1 doi:10.1152/ajplung.00454.2006

Inner city children exposed to high levels of ozone suffer from an increased prevalence of respiratory diseases. Lung development in children is a long-term process, and there is a significant period of time during development when children growing up in urban areas are exposed to oxidant air pollution. This study was designed to test whether repeating cycles of injury and repair caused by episodes of ozone exposure lead to chronic airway disease and decreased lung function by altering normal lung maturation. We evaluated postnatal lung morphogenesis and function of infant monkeys after 5 mo of episodic exposure of 0.5 parts per million ozone beginning at 1 mo of age. Nonhuman primates were chosen because their airway structure and postnatal lung development is similar to those of humans. Airway morphology and structure were evaluated at the end of the 5-too exposure period. Compared with control infants, ozone-exposed animals had four fewer nonalveolarized airway generations, hyperplastic bronchiolar epithelium, and altered smooth muscle bundle orientation in terminal and respiratory bronchioles. These results suggest that episodic exposure to environmental ozone compromises postnatal morphogenesis of tracheobronchial airways. oxidant air pollution; adverse effects; growth and development; lung

Development of the basement membrane zone (BMZ) occurs postnatally in the rhesus monkey. The purpose of this study was to determine whether house dust mite allergen (HDMA) plus ozone altered this process. Rhesus monkeys were exposed to a regimen of HDMA and/or ozone or filtered air for 6 mo. To detect structural changes in the BMZ, we measured immunoreactivity of collagen I. To detect functional changes in the BMZ, we measured perlecan and fibroblast growth factor-2 (FGF-2). We also measured components of the FGF-2 ternary signaling complex [fibroblast growth factor receptor-1 (FGFR-1) and syndecan-4]. The width of the BMZ was irregular in the ozone groups, suggesting atypical development of the BMZ. Perlecan was also absent from the BMZ. In the absence of perlecan, FGF-2 was not bound to the BMZ. However, FGF-2 immunoreactivity was present in basal cells, the lateral intercellular space (LIS), and attenuated fibroblasts. FGFR-1 immunoreactivity was downregulated, and syndecan-4 immunoreactivity was upregulated in the basal cells. This suggests that FGF-2 in basal cells and LIS may be bound to the syndecan-4. We conclude that ozone and HDMA plus ozone effected incorporation of perlecan into the BMZ, resulting in atypical development of the BMZ. These changes are associated with specific alterations in the regulation of FGF-2, FGFR-1, and syndecan-4 in the airway epithelial-mesenchyreal trophic unit, which may be associated with the developmental problems of lungs associated with exposure to ozone. perlecan; fibroblast growth factor-2; fibroblast growth factor receptor-1; syndecan-4; epithelial-mesenchymal trophic unit

Thickening of the basement membrane zone (BMZ) is a characteristic of several airway diseases; however, very little is known about how this process occurs. The purpose of this study was to define development of the BMZ in the trachea of growing rhesus monkeys at 1, 2, 3, and 6 mo of age. We measured immunoreactivity of collagen types I, III, and V to detect structural changes in the developing BMZ. To detect more dynamic, functional components of the epithelial-mesenchymal trophic unit, we evaluated the distribution of perlecan, fibroblast growth factor-2 (FGF-2), and fibroblast growth factor receptor-1 (FGFR-1). One-month-old monkeys had a mean collagen BMZ width of 1.5 [+ or -] 0.7 [micro]m that increased to 4.4 [+ or -] 0.4 [micro]m in 6-mo-old monkeys. Perlecan was localized in the BMZ of the epithelium at all ages. FGF-2 was strongly expressed in basal cells at 1-3 mo. At 6 mo, FGF-2 was expressed throughout the BMZ and weakly in basal cells. FGFR-1 immunoreactivity was expressed by basal cells and cilia and weakly in the nuclei of columnar cells at all time points. These data indicate that development of the BMZ is a postnatal event in the rhesus monkey that involves FGF-2. basal cell; perlecan; fibroblast growth factor receptor-1; rhesus monkey

Humans are widely exposed to polycyclic aromatic hydrocarbons, commonly found in cigarette smoke and diesel exhaust. These can undergo site- and cell-specific metabolism to cytotoxic intermediates. Metabolism of naphthalene and Clara cell cytotoxicity have been extensively studied in male animals. To address whether male and female mice are equally susceptible to naphthalene, mice were injected with naphthalene, and lungs were examined 1, 2, 3, 6, and 24 h after treatment. By analysis of acute injury using differential permeability to fluorescent nuclear dyes and high-resolution histopathology, injury in female mice was found to be more extensive, occur earlier, and include permeable cells in proximal airways, including airway bifurcations. HPLC analysis of the products of cytochrome P-450 (CYP)-mediated metabolism in microdissected airways indicated that although both genders produced a predominance of products from CYP2F2, female mice produced more naphthalene dihydrodiol in distal airways, the primary sites of injury. We conclude that there are clear gender differences in susceptibility to naphthalene-induced injury and that differences in metabolism of naphthalene may play a role in elevated susceptibility in female mice. cytochrome P-450; sex; female; mice; Clara cell

The effect of naphthalene-induced cytotoxic injury on terminal bronchiolar epithelial repair in rabbit Clara cells was investigated. Clara cells are nonciliated secretory cells believed to be the progenitor of bronchiole epithelium cells. The results show that cell repair entails cell proliferation in the epithelial cells and the interstitial compartment followed by epithelial cell differentiation.

BACKGROUND: The potential carcinogenicity of naphthalene (NA), a ubiquitous environmental pollutant, in human respiratory tract is a subject of intense debate. Chief among the uncertainties in risk assessment for NA is whether human lung CYP2A13 and CYP2F1 can mediate NA's respiratory tract toxicity. OBJECTIVES: We aimed to assess the in vivo function of CYP2A13 and CYP2F1 in NA bioactivation and NA-induced respiratory tract toxicity in mouse models. METHODS: Rates of microsomal NA bioactivation and the effects of an anti-CYP2A antibody were determined for lung and nasal olfactory mucosa (OM) from Cyp2abfgs-null, CYP2A13-humanized, and CYP2A13/2F1-humanized mice. The extent of NA respiratory toxicity was compared among wild-type, Cyp2abfgs-null, and CYP2A13/2F1-humanized mice following inhalation exposure at an occupationally relevant dose (10 ppm for 4 hr). Results: In vitro studies indicated that the NA bioactivation activities in OM and lung of the CYP2A13/2F1-humanized mice were primarily contributed by, respectively, CYP2A13 and CYP2F1. CYP2A13/2F1-humanized mice showed greater sensitivity to NA than Cyp2abfgs-null mice, with greater depletion of nonprotein sulfhydryl and occurrence of cytotoxicity (observable by routine histology) in the OM, at 2 or 20 hr after termination of NA exposure, in humanized mice. Focal, rather than gross, lung toxicity was observed in Cyp2abfgs-null and CYP2A13/2F1-humanized mice; however, the extent of NA-induced lung injury (shown as volume fraction of damaged cells) was significantly greater in the terminal bronchioles of CYP2A13/2F1-humanized mice than in Cyp2abfgs-null mice. CONCLUSION: CYP2F1 is an active enzyme. Both CYP2A13 and CYP2F1 are active toward NA in the CYP2A13/2F1-humanized mice, where they play significant roles in NA-induced respiratory tract toxicity. https://doi.org/10.1289/EHP844., Introduction Naphthalene (NA), commonly found in diesel exhaust, biomass burning, and tobacco smoke (Kakareka and Kukharchyk 2003; U.S. EPA 1986; Witschi et al. 1997), is an important environmental pollutant. The [...]