Surfactant Protein D Deficiency Increases Lung Injury during Endotoxemia

ArticleinAmerican Journal of Respiratory Cell and Molecular Biology 44(5):709-15 · May 2011with11 Reads
DOI: 10.1165/rcmb.2009-0436OC · Source: PubMed
Abstract
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are major causes of acute respiratory failure with high rates of morbidity and mortality. Although surfactant protein (SP)-D plays a critical role in pulmonary innate immunity and several clinical studies suggest that this protein may be implicated in the pathophysiology of ARDS, little is known regarding the function of SP-D in ARDS. In the present study, we induced indirect lung injury by intraperitoneal injection of LPS and direct lung injury by intratracheal injection of LPS in wild-type and Sftpd(-/-) mice to elucidate the role of SP-D during ALI/ARDS. Results indicate that pulmonary levels of IL-6 and TNF-α were higher in Sftpd(-/-) mice when compared with wild-type mice. However, the magnitude of this difference was 10-fold greater after indirect lung injury compared with direct lung injury. After indirect lung injury, there was a 2-fold increase in the number of pulmonary monocyte/macrophages in the Sftpd(-/-) mice when compared with wild-type mice, whereas pulmonary neutrophils were not increased. After indirect injury, the concentration of granulocyte-macrophage colony stimulating factor (GM-CSF) was approximately 5-fold greater in Sftpd(-/-) mice than wild-type mice. In contrast, after direct injury, the concentration of GM-CSF was 20-fold less in Sftpd(-/-) mice than wild-type mice. Despite increased inflammatory cells and markers of inflammation, survival in Sftpd(-/-) mice after indirect lung injury was paradoxically increased. In conclusion, these results suggest that SP-D inhibits pulmonary inflammation and migration of peripheral monocyte/macrophages into the lung through GM-CSF-dependent pathways during indirect lung injury.
    • "Whether the magnitude of bile acid level increase or a synergetic effect of bile acids and TNF-a after CBDL contribute to the selective alterations in AT2 cells after CBDL are not defined. In addition, increased mononuclear cell infiltration in the lung is associated with decreased surfactant protein production in some inflammatory pulmonary diseases [53,54]. In experimental HPS, monocytes are recruited to the pulmonary intravascular space via altered chemokine/receptor expression (such as fractalkine/CX3CL1) [55]. "
    [Show abstract] [Hide abstract] ABSTRACT: The hepatopulmonary syndrome (HPS) develops when pulmonary vasodilatation leads to abnormal gas exchange. However, in human HPS, restrictive ventilatory defects are also observed supporting that the alveolar epithelial compartment may also be affected. Alveolar type II epithelial cells (AT2) play a critical role in maintaining the alveolar compartment by producing four surfactant proteins (SPs, SP-A, SP-B, SP-C and SP-D) which also facilitate alveolar repair following injury. However, no studies have evaluated the alveolar epithelial compartment in experimental HPS. In this study, we evaluated the alveolar epithelial compartment and particularly AT2 cells in experimental HPS induced by common bile duct ligation (CBDL). We found a significant reduction in pulmonary SP production associated with increased apoptosis in AT2 cells after CBDL relative to controls. Lung morphology showed decreased mean alveolar chord length and lung volumes in CBDL animals that were not seen in control models supporting a selective reduction of alveolar airspace. Furthermore, we found that administration of TNF-α, the bile acid, chenodeoxycholic acid, and FXR nuclear receptor activation (GW4064) induced apoptosis and impaired SP-B and SP-C production in alveolar epithelial cells in vitro. These results imply that AT2 cell dysfunction occurs in experimental HPS and is associated with alterations in the alveolar epithelial compartment. Our findings support a novel contributing mechanism in experimental HPS that may be relevant to humans and a potential therapeutic target.
    Full-text · Article · Nov 2014
    • "SP-A promotes surfactant lipid turnover by mediating surfactant uptake by type II cells [83]. SP-D also helps regulate surfactant degradation by macrophages and type II cells, as evidenced by the observation that this function is impaired in SP-D-deficient mice [84, 85]. The majority of surfactant lipid is phosphatidylchoUne, with phosphatidylglycerol and phosphatidylethanolamine as the other major phospholipids present [86]. "
    [Show abstract] [Hide abstract] ABSTRACT: The distal airways are covered with a heterogeneous layer of cells known as the alveolar epithelium. Alveolar epithelial cells provide the major barrier between the airspace and fluid filled tissue compartments. As such, regulation of the alveolar epithelium is critical to maintain a healthy lung and for optimal gas exchange. In this chapter, we discuss functional roles for alveolar epithelial cells with particular emphasis on intercellular junctions and communication. As a thin layer of cells directly exposed to atmospheric oxygen, alveoli are particularly sensitive to oxidant insults. Alcohol significantly diminishes the normal antioxidant reserves of the alveolar epithelium, thereby rendering it sensitized for an exaggerated damage response to acute and chronic injuries. The effects of alcohol on alveolar epithelia are discussed along with open questions and potential therapeutic targets to prevent the pathophysiology of alcoholic lung disease.
    Chapter · Jan 2014 · PLoS ONE
    • "6) Accelerates the activity of macrophages for Phagocytosis of apoptotic cells and in turn promotes the anti-inflammatory response of macrophages [182,183]. SP-A and SP-D are known to specifically modulate the intensities of inflammatory mediators in utero that involve preterm birth [184,185] and acute respiratory distress syndrome [186]. Although the main function of Lung surfactants is to regulate the pressure differential throughout the respiratory cycle, yet research has shown that the role they play in immune defense is not trivial. "
    [Show abstract] [Hide abstract] ABSTRACT: The lungs undergo an extensive endodermal diverging morphogenesis along with alveogenesis, angiogenesis, and vasculogenesis to secure a sufficient diffusion surface for gaseous exchange. Any aberration in the course of normal development inculcating structural and functional abnormalities of lungs in antenatal life has potential morbidity in adult life. Factors such as IUGR, nutrient deficiency, FLM, Hypoxemia, ETS, surfactant deficiency, allergy and infections can adversely affect in-utero lungs development. Peculiar local and systemic inflammatory immune responses may elicit persistent architectural and physiological abnormalities. Lung surfactant produced by AEC-II cells is a mixture of phospholipids, surfactant proteins, and neutral lipids. Surfactant lowers alveolar surface tension, a crucial step for the prevention of alveolar collapse. Surfactant proteins are part of the innate immune defense of the lung. Surfactant deficiency and dysfunction is known to implicate a number of respiratory diseases especially allergic asthma and NRDS. The present article provides a state of the art review of the current knowledge of biology of normal lung development, its anatomical and molecular aspects, factors that regulate normal organogenesis of pulmonary system and molecular basis of respiratory allergic disorders including asthma.
    Full-text · Article · Jan 2013
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