Surfactant protein-D (Sftpd) is a pulmonary collectin important in down regulating macrophage inflammatory responses. In these studies we analyzed the effects of chronic macrophage inflammation due to loss of Sftpd on the persistence of ozone-induced injury, macrophage activation, and altered functioning in the lung. Wild type (Sftpd+/+) and Sftpd-/- mice (8 wk) were exposed to air or ozone (0.8 ppm, 3 h). Bronchoalveolar lavage fluid (BAL) and tissue were collected 72 h later. In Sftpd-/- mice, but not Sftpd+/+ mice, increased BAL protein and nitrogen oxides were observed following ozone inhalation indicating prolonged lung injury and oxidative stress. Increased numbers of macrophages were also present in BAL and in histologic sections from Sftpd-/- mice. These cells were enlarged and foamy suggesting that they are activated. This is supported by findings of increased BAL chemotactic activity, and increased expression of inducible nitric oxide synthase in lung macrophages. In both Sftpd+/+ and Sftpd-/- mice, inhalation of ozone was associated with functional alterations in the lung. Whereas this was limited to central airway mechanics in Sftpd+/+ mice, both central airway and parenchymal mechanics were modified by ozone exposure in Sftpd-/- mice. Most notable changes were in resistance and elastance spectra and baseline lung functioning, in lung responsiveness to changes in positive end-expiratory pressure. These data demonstrate that loss of Sftpd is associated with prolonged lung injury, oxidative stress and macrophage accumulation and activation in response to ozone, and more extensive functional changes consistent with the loss of parenchymal integrity.
"Based on asymptotic and frequency-dependent behavior of Z rs data in the b20 Hz frequency range, empiric functions have been used for independent characterization of R L and E L (Groves et al., 2012). A rational equation was chosen to model R L due to its ability to reliably represent the high frequency asymptote with a single parameter while characterizing the magnitude and curvature of the frequency-dependent change: "
[Show abstract][Hide abstract] ABSTRACT: Acute Cl2 exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl2 inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6 J mice underwent whole-body exposure to an effective 60 ppm-hour Cl2 dose, and were sacrificed 3, 24 and 48 hours later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 hours, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 hours. Cl2 exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO3- or NO2-. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl2 exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 hours, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl2 inhalation.
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is associated with persistent inflammation and oxidative stress in susceptible individuals. Using microarray analysis of bronchial biopsy samples from patients with COPD and controls, we identified Wnt4 as being up-regulated in COPD. Analysis of bronchial biopsy samples showed a very strong correlation between Wnt4 and IL8 gene expression, suggesting that Wnt4 plays a role in chronic lung inflammation. In vitro, Wnt4 induced proliferation and inflammation in human epithelial cells (BEAS-2B) and normal primary human bronchial epithelial cells in a concentration-dependent manner. This effect was enhanced in the presence of interleukin-1β (IL-1β) as a result of activation of the p38 and c-Jun NH2-terminal kinase mitogen-activated protein kinase pathways. Hydrogen peroxide, but not proinflammatory stimuli, up-regulated Wnt4 expression in epithelial cells. In monocytic THP-1 and primary airway smooth muscle cells, Wnt4 induced inflammation and enhanced the inflammatory response to lipopolysaccharide and IL-1β but did not induce proliferation. In addition, these other cell types did not have enhanced Wnt4 expression in response to hydrogen peroxide. Our results indicate that airway epithelial activation, due to oxidative stress, may lead to Wnt4 induction. Wnt4, in turn, acts through the noncanonical pathway to activate epithelial cell remodeling and IL8 gene expression, leading to neutrophil infiltration and inflammation.-Durham, A. L., McLaren, A., Hayes, B. P., Caramori, G., Clayton, C. L., Barnes, P. J., Chung, K. F., Adcock, I. M. Regulation of Wnt4 in chronic obstructive pulmonary disease.
The FASEB Journal 03/2013; 27(6). DOI:10.1096/fj.12-217083 · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In these studies, we analyzed the effects of ozone on bronchiolar epithelium. Exposure of rats to ozone (2 ppm, 3 h) resulted in rapid (within 3 h) and persistent (up to 72 h) histological changes in the bronchiolar epithelium including hypercellularity, loss of cilia, and necrotizing bronchiolitis. Perivascular edema and vascular congestion were also evident, along with decreases in Clara cell secretory protein in bronchoalveolar lavage, which was maximal 24 h post exposure. Ozone also induced the appearance of 8-hydroxy-2'-deoxyguanosine, Ym1 and heme oxygenase-1 in the bronchiolar epithelium. This was associated with increased expression of cleaved caspase-9 and beclin-1, indicating initiation of apoptosis and autophagy. A rapid and persistent increase in galectin-3, a regulator of epithelial cell apoptosis, was also observed. Following ozone exposure (3-24 h) increased expression of cyclooxygenase-2, inducible nitric oxide synthase and arginase-1 was noted in bronchiolar epithelium. Ozone-induced injury and oxidative stress in bronchiolar epithelium were linked to methacholine-induced alterations in pulmonary mechanics. Thus, significant increases in lung resistance and elastance, along with decreases in lung compliance and end tidal volume were observed at higher doses of methacholine. This indicates that ozone causes an increase in effective stiffness of the lung, as a consequence of changes in the conducting airways. Collectively, these studies demonstrate that bronchiolar epithelium is highly susceptible to injury and oxidative stress induced by acute exposure to ozone; moreover, this is accompanied by altered lung functioning.
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