Surfactant Protein D Regulates Airway Function and Allergic Inflammation through Modulation of Macrophage Function

Takeda, Katsuyuki; Miyahara, Nobuaki; Rha, Yeong Ho; Taube, Christian; Yang, Eun Young; Joetham, Anthony; Kodama, Taku; Balhorn, Annette; Dakhama, Azzeddine; Duez, Catherine; Evans, Alice; Voelker, Dennis R.; Gelfand, Erwin W.

doi:10.1164/rccm.200304-548oc

Cited by 71 publications

(68 citation statements)

References 48 publications

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“…Taken together, these results indicate that lung function is significantly altered by both a loss of Sftpd and by ozone exposure, and that an interaction between these proinflammatory stimuli occurs. These results support findings in other models of lung injury that Sftpd is important in maintaining normal lung functioning (38,(41)(42)(43).…”

Section: Discussionsupporting

confidence: 90%

Prolonged Injury and Altered Lung Function after Ozone Inhalation in Mice with Chronic Lung Inflammation

Groves

Gow

Massa

et al. 2012

Am J Respir Cell Mol Biol

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Surfactant protein-D (Sftpd) is a pulmonary collectin important in down-regulating macrophage inflammatory responses. In these experiments, we analyzed the effects of chronic macrophage inflammation attributable to loss of Sftpd on the persistence of ozoneinduced injury, macrophage activation, and altered functioning in the lung. Wild-type (Sftpd 1/1 ) and Sftpd 2/2 mice (aged 8 wk) were exposed to air or ozone (0.8 parts per million, 3 h). Bronchoalveolar lavage (BAL) fluid and tissue were collected 72 hours later. In Sftpd 2/2 mice, but not Sftpd 1/1 mice, increased BAL protein and nitrogen oxides were observed after ozone inhalation, indicating prolonged lung injury and oxidative stress. Increased numbers of macrophages were also present in BAL fluid and in histologic sections from Sftpd 2/2 mice. These cells were enlarged and foamy, suggesting that they were activated. This conclusion was supported by findings of increased BAL chemotactic activity, and increased expression of inducible nitric oxide synthase in lung macrophages. In both Sftpd 1/1 and Sftpd 2/2 mice, inhalation of ozone was associated with functional alterations in the lung. Although these alterations were limited to central airway mechanics in Sftpd 1/1 mice, both central airway and parenchymal mechanics were modified by ozone exposure in Sftpd 2/2 mice. The most notable changes were evident in resistance and elastance spectra and baseline lung function, and in lung responsiveness to changes in positive endexpiratory pressure. These data demonstrate that a loss of Sftpd is associated with prolonged lung injury, oxidative stress, and macrophage accumulation and activation in response to ozone, and with more extensive functional changes consistent with the loss of parenchymal integrity. Keywords: ozone; surfactant protein-D; macrophages; iNOS; lung functionOzone is a ubiquitous urban air pollutant generated as a component of photochemical smog. Inhaled ozone causes ozonation and the peroxidation of proteins and lipids in the epithelial lining fluid layer of the lung, resulting in the production of oxidized proteins, aldehydes, and free radicals, which can damage surrounding tissue (1, 2). This is accompanied by an accumulation of activated macrophages in the lung and the production of additional cytotoxic and proinflammatory mediators, including reactive oxygen and reactive nitrogen species (ROS and RNS, respectively) that contribute to tissue injury (3). Airway and tissue mechanics are also altered after ozone exposure. Thus, in humans, ozone inhalation leads to a deterioration of pulmonary function, as measured by decreases in respiratory frequency, forced expiratory volume in 1 second, and forced vital capacity, and increases in airway resistance (1,4,5). Ozone has been shown to exacerbate asthma and increase airway hyperreactivity (5, 6), and to contribute to increased morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD) (7,8). Similar alterations in lung function and increases in sensitivity to ozone have b...

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Section: Discussionsupporting

confidence: 90%

Prolonged Injury and Altered Lung Function after Ozone Inhalation in Mice with Chronic Lung Inflammation

Groves

Gow

Massa

et al. 2012

Am J Respir Cell Mol Biol

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“…Next we investigated mechanisms potentially contributing to this increased airway resistance including a-smooth muscle actin and mucous increases, because these factors have been suggested to contribute to airway hyperresponsiveness in asthma models (36)(37)(38). We immunostained lung tissue from BALB Cftr tm1UNC and WT mice for a-smooth muscle actin and with PAS staining to visualize mucus, with established methods (36-38).…”

Section: Resultsmentioning

confidence: 99%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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We previously observed the lungs of naive BALB/cJ Cftrtm1UNC mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftrtm1UNC mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftrtm1UNC mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftrtm1UNC mice had more CD3+ (both CD4+ and CD8+) cells than did littermates or C57BL/6J Cftrtm1UNC mice. Cftrtm1UNC and littermate mice of either strain did not differ in anti-CD3–stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftrtm1UNC mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftrtm1UNC mice demonstrated increased Il-17 secretion. BALB Cftrtm1UNC mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftrtm1UNC mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftrtm1UNC mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.

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“…The evidence from those studies suggests that IL-10 influences or acts in concert with one or more inflammatory factors to increase smooth muscle activity (31), perhaps involving airway smooth muscle autocrine signaling through IL-5 (33) or regulation of surfactant protein D (35). However, there has been no further consensus.…”

Section: Association Of Il-10 and Airway Responsivenessmentioning

confidence: 99%

Alterations in Nitric Oxide and Cytokine Production with Airway Inflammation in the Absence of IL-10

Ameredes

Zamora

Sethi

et al. 2005

The Journal of Immunology

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IL-10 is an anti-inflammatory cytokine that suppresses NO synthase (NOS) and production of NO; its lack may promote NO production and alterations in cytokines modulated by NO with allergic airway inflammation (AI), such as IL-18 and IL-4. Therefore, we induced AI in IL-10 knockout (−/−) and IL-10-sufficient C57BL/6 (C57) mice with inhaled OVA and measured airway NO production, as exhaled NO (ENO) and bronchoalveolar lavage fluid nitrite levels. ENO and nitrite levels were elevated significantly in naive IL-10−/− mice as compared with C57 mice. With AI, ENO and nitrite levels increased in C57 mice and decreased in IL-10−/− mice. IL-18 production fell with both AI and addition of S-nitroso-N-acetyl-d,l-penicillamine (a NO donor) but was not significantly increased by chemical NOS inhibition by l-N5-(1-iminoethyl)-ornithine. IL-4 AI was increased significantly (up to 10-fold greater) in the absence of IL-10 but was reduced significantly with chemical inhibition of NOS. Airway responsiveness was lower in IL-10−/− mice and was associated with alteration in production of NO and IL-4. Thus, IL-4 production was increased, and likely decreased NO production, in a way not predicted by the absence of IL-10. Inhibition of IL-4 production, with inhibition of NOS in the absence of IL-10, demonstrated the importance of a NO and IL-4 feedback mechanism regulating this interaction.

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Surfactant Protein D Regulates Airway Function and Allergic Inflammation through Modulation of Macrophage Function

Cited by 71 publications

References 48 publications

Prolonged Injury and Altered Lung Function after Ozone Inhalation in Mice with Chronic Lung Inflammation

Prolonged Injury and Altered Lung Function after Ozone Inhalation in Mice with Chronic Lung Inflammation

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Alterations in Nitric Oxide and Cytokine Production with Airway Inflammation in the Absence of IL-10

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