Decreased Surfactant Protein-B Expression and Surfactant Dysfunction in a Murine Model of Acute Lung Injury (original) (raw)
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Surfactant-associated protein A inhibits LPS-induced cytokine and nitric oxide production in vivo
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2000
The role of surfactant-associated protein (SP) A in the mediation of pulmonary responses to bacterial lipopolysaccharide (LPS) was assessed in vivo with SP-A gene-targeted [SP-deficient; SP-A(−/−)] and wild-type [SP-A(+/+)] mice. Concentrations of tumor necrosis factor (TNF)-α, macrophage inflammatory protein-2, and nitric oxide were determined in recovered bronchoalveolar lavage fluid after intratracheal administration of LPS. SP-A(−/−) mice produced significantly more TNF-α and nitric oxide than SP-A(+/+) mice after LPS treatment. Intratracheal administration of human SP-A (1 mg/kg) to SP-A(−/−) mice restored regulation of TNF-α, macrophage inflammatory protein-2, and nitric oxide production to that of SP-A(+/+) mice. Other markers of lung injury including bronchoalveolar fluid protein, phospholipid content, and neutrophil numbers were not influenced by SP-A. Data from experiments designed to test possible mechanisms of SP-A-mediated suppression suggest that neither binding of LPS...
Pulmonary surfactant and inflammation in septic adult mice: role of surfactant protein A
Journal of applied physiology (Bethesda, Md. : 1985), 2002
Surfactant alterations, alveolar cytokine changes, and the role of surfactant protein (SP)-A in septic mice were investigated. Sepsis was induced via cecal ligation and perforation (CLP). Septic and sham mice were euthanized at 0, 3, 6, 9, 12, 15, and 18 h after surgery. Mice deficient in SP-A and mice that overexpressed SP-A were euthanized 18 h after surgery. In wild-type, sham-operated mice, surfactant pool sizes were similar at all time points, whereas in the CLP groups there was a significant decrease in small-aggregate surfactant pool sizes beginning 6 h after CLP. Interleukin-6 concentrations in bronchoalveolar lavage fluid from septic animals increased from 6 to 18 h after surgery. Identical surfactant alterations and concentrations of cytokines were observed in septic mice that were SP-A deficient or that overexpressed SP-A. In conclusion, alterations of pulmonary surfactant and alveolar cytokines occur simultaneously, 6 h after a systemic insult. In addition, we did not de...
Faseb Journal, 2004
Acute respiratory distress syndrome (ARDS) is a life-threatening ailment characterized by severe lung injury involving inflammatory cell recruitment to the lung, cytokine production, surfactant dysfunction, and up-regulation of nitric oxide synthase 2 (NOS2) resulting in nitric oxide (NO) production. We hypothesized that NO production from NOS2 expressed in lung parenchymal cells in a murine model of ARDS would correlate with abnormal surfactant function and reduced surfactant protein-B (SP-B) expression. Pulmonary responses to nebulized endotoxin (lipopolysaccharide, LPS) were evaluated in wild-type (WT) mice, NOS2 null (−/−) mice, and NOS2-chimeric animals derived from bone marrow transplantation. NOS2 −/− animals exhibited significantly less physiologic lung dysfunction and loss of SP-B expression than did WT animals. However, lung neutrophil recruitment and bronchoalveolar lavage cytokine levels did not significantly differ between NOS2 −/− and WT animals. Chimeric animals for NOS2 exhibited the phenotype of the recipient and therefore demonstrated that parenchymal production of NOS2 is critical for the development of LPS-induced lung injury. Furthermore, administration of NO donors, independent of cytokine stimulation, decreased SP-B promoter activity and mRNA expression in mouse lung epithelial cells. This study demonstrates that expression of NOS2 in lung epithelial cells is critical for the development of lung injury and mediates surfactant dysfunction independent of NOS2 inflammatory cell expression and cytokine production.
Surfactant proteins and the inflammatory and immune response in the lung
2009
Surfactant proteins are important for regulating surfactant activity and innate host defence; in particular, polymorphisms in intron 4 of the SP-B gene and dominant mutations of SP-C have been associated with bronchopulmonary dysplasia. The innate immune system is older and consists of soluble proteins, which bind microbial products and phagocytic leukocytes resembling primitive amebae, which float through the bloodstream and migrate into tissues at sites of inflammation, or reside in tissue waiting for foreign material. The innate immune system is always active and is immediately responsive, ready to recognize and inactivate microbial products entering lungs and other tissues. Pro-inflammatory cytokines (interleukins IL-1β, IL-6 and soluble ICAM-1) are present in lung lavage fluid from day 1 in premature infants with respiratory distress and reach a peak in the second week. IL-1β induces the release of inflammatory mediators, activating inflammatory cells and up-regulating adhesion...
EFFECT OF SURFACTANT PROTEIN A (SPA) ON THE PRODUCTION OF CYTOKINES BY HUMAN PULMONARY MACROPHAGES
Shock, 2000
Surfactant protein A (SP-A) is thought to play a role in the modulation of lung inflammation during acute respiratory distress syndrome (ARDS). However, SP-A has been reported both to stimulate and to inhibit the proinflammatory activity of pulmonary macrophages (M). Because of the interspecies differences and heterogeneity of M subpopulations used may have influenced previous controversial results, in this study, we investigated the effect of human SP-A on the production of cytokines and other inflammatory mediators by two well-defined subpopulations of human pulmonary M. Surfactant and both alveolar (aM) and interstitial (iM) macrophages were obtained from multiple organ donor lungs by bronchoalveolar lavage and enzymatic digestion. Donors with either recent history of tobacco smoking, more than 72 h on mechanical ventilation, or any radiological pulmonary infiltrate were discarded. SP-A was purified from isolated surfactant using sequential butanol and octyl glucoside extractions. After 24-h preculture, purified M were cultured for 24 h in the presence or absence of LPS (10 µg/mL), SP-A (50 µg/mL), and combinations. Nitric oxide and carbon monoxide (CO) generation (pmol/µg protein), cell cGMP content (pmol/µg protein), and tumor necrosis factor alpha (TNF␣), interleukin (IL)-1, and IL-6 release to the medium (pg/µg protein) were determined. SP-A inhibited the lipopolysaccharide (LPS)-induced TNF␣ response of both interstitial and alveolar human M, as well as the IL-1 response in iM. The SP-A effect on TNF␣ production could be mediated by a suppression in the LPS-induced increase in intracellular cGMP. In iM but not in aM, SP-A also inhibited the LPS-induced IL-1 secretion and CO generation. These data lend further credit to a physiological function of SP-A in regulating alveolar host defense and inflammation by suggesting a fundamental role of this apoprotein in limiting excessive proinflammatory cytokine release in pulmonary M during ARDS.
Surfactant protein A (SP-A) is decreased in acute parenchymal lung injury associated with polytrauma
European Journal of Clinical Investigation, 1992
To further investigate if the pulmonary surfactant system is altered in acute parenchymal lung injury of adults following polytrauma we measured SP-A level and phospholipid composition in 150 sequentially obtained lung lavage samples from polytraumatized patients (n= 19) beginning at the day of trauma and ending 18 days later or when the patient was extubated. Out of the 19 patients studied 10 had severe parenchymal lung injury (ARDS), nine had moderate lung injury. SP-A was measured using a twomonoclonal sandwich ELISA-assay. Phospholipids were separated using high-performance liquid chromatography and their composition was calculated by comparison with standard phospholipid mixtures. We found immunoreactive SP-A concentrations ranging from 0.1 pg ml-' to 8.5 pg ml-' lung lavage fluid obtained from all patients. The mean SP-A concentration in patients who had severe parenchymal lung injury (ARDS) was 1.06f0.16 pg ml-' lavage fluid, the mean concentration in patients who had only moderate parenchymal lung injury was 1.92 k 0.18 pg ml-' lavage fluid. Both concentrations were lower than in healthy controls (2.74k0.3 pg ml-' lavage fluid; n = 12). In patients who had moderate lung injury the SP-A level normalized, but in patients who had severe lung injury the SP-A level remained low during the timespan examined. SP-A alterations did not correlate to changes in phospholipid composition as determined in lung lavage samples of individual patients. We conclude that alveolar SP-A concentrations decrease in polytraumatized patients who have acute parenchymal lung injury soon after the trauma occurs. In patients who have lung injury of low severity the SP-A level normalizes with recovery, but with more severe parenchymal lung injury SP-A levels remain low. We speculate that the metabolic regulation of individual surfactant components might differ during lung injury and repair
Early Alterations in Intracellular and Alveolar Surfactant of the Rat Lung in Response to Endotoxin
American Journal of Respiratory and Critical Care Medicine, 1998
The aim of this study was to characterize early ultrastructural, biochemical, and functional alterations of the pulmonary surfactant system induced by Salmonella minnesota lipopolysaccharide (LPS) in rat lungs. Experimental groups were: (1) control in vitro , 150 min perfusion; (2) LPS in vitro , 150 min perfusion, infusion of 50 g/ml LPS after 40 min; (3) control ex vivo , 10 min perfusion; (4) LPS ex vivo , lungs perfused for 10 min from rats treated for 110 min with 20 mg/kg LPS intraperitoneally. Morphometry of type II pneumocytes showed that LPS increased stored surfactant. Lamellar bodies were increased in size, but decreased in numerical density, suggesting that giant lamellar bodies observed in LPS-treated lungs may result from fusion of normal bodies. Structural analysis of alveolar surfactant composition showed that LPS elicited an increase in lamellar body-like and multilamellar forms. Bronchoalveolar lavage (BAL) material from LPS-treated lungs was decreased in phospholipids. BAL bubble surfactometer analysis showed a reduction in hysteresis area caused by LPS. We conclude that LPS leads to alterations of intracellular and alveolar surfactant within 2 h: fusion of lamellar bodies, reduction in surfactant secretion, and changes in alveolar surfactant transformation, composition, and function, which may contribute to the development of respiratory distress. Fehrenbach H, Brasch F, Uhlig S, Weisser M, Stamme C, Wendel A, Richter J. Early alterations in intracellular and alveolar surfactant of the rat lung in response to endotoxin.
Altered regulation of surfactant phospholipid and protein A during acute pulmonary inflammation
Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1995
Biochemical changes in the pulmonary surfactant system caused by exposure to toxicants are often accompanied by an influx of inflammatory cells into the lungs. We have investigated the possibility that the inflammatory and surfactant biochemical effects might be connected. Co-treatment with dexamethasone, a synthetic anti-inflammatory glucocorticoid, mitigated the increases in free cells and total intracellular surfactant phospholipid normally seen in animals given silica alone, suggesting a relationship between the free cell population of the alveoli and the surfactant system during alveolitis. Furthermore, we have investigated whether induction of the surfactant system is a universal response to alveolar inflammation. Inflammation was induced in the lungs by intratracheal injections of titanium dioxide, silica, bleomycin or lipopolysaccharide (LPS) suspended in isotonic saline. Inflammatory cell and surfactant responses were measured at 3 days and 14 days following injection. There was a distinct alveolar inflammatory cell profile following administration of each agent, at each time point, indicating a dynamic inflammatory cell population during the course of the study. Furthermore, surfactant phospholipid and protein A (SP-A) pools exhibited unique responses to the inflammatory agents. Only silica-treated lungs maintained elevated levels of surfactant phospholipids and SPA throughout the course of the experiment. We conclude that both the surfactant components and the inflammatory cell population of the alveoli undergo dynamic changes following treatment with these inflammatory agents and that activation of the surfactant system is not a universal response to alveolar inflammation, since surfactant components were not always elevated during times of increased alveolar cellularity. The unique inflammatory cell infiltrate elicited by silica is of particular interest in that surfactant components were elevated throughout the course of the experiment in this group. Indeed, we have shown that the size of the intracellular pool of surfactant is directly proportional to the number of polymorphonuclear leukocytes but not alveolar macrophages or lymphocytes in the alveoli following silica treatment. Finally, our data suggest that the phospholipid and SPA components of surfactant respond differentially to the pulmonary toxicants in this study.
American Journal of Biomedical Sciences, 2010
To determine the possible contribution of apoptosis in the pathogenesis of ARDS, we investigated the role of exogenous surfactant in a rodent model of ARDS after intratracheal instillation of lipopolysaccharide. Adult male Sprague Dawley rats were divided into four groups: buffer controls; rats challenged with LPS (055:B5 E.coli); challenged with LPS and treated with porcine surfactant (P-SF); and challenged with LPS and treated with synthetic surfactant (S-SF). Parameters of lung injury and inflammation were assessed 72h after treatment. We demonstrated that intratracheal administration of LPS could provoke significant lung injury, which was characterized by increase of MPO activity, wet/dry lung weight ratio, cytokine levels in bronchoalveolar lavage fluid (BALF), apoptosis of BALF cells and caspase-3 activity in lung tissue. Intratracheally delivered surfactant significantly reduced the parameters of LPS-induced inflammation: infiltration of inflammatory cells into lung tissue and BALF, pulmonary edema, lung myeloperoxidase activity, lipid peroxidation, caspase-3 activity, number of apoptotic BALF cells, lactate dehydrogenase level & pro-inflammatory cytokines levels. Taken together, the present data demonstrate that exogenous surfactant systemically attenuates lipopolysaccharide-induced inflammation.