Pulmonary surfactant and inflammation in septic adult mice: role of surfactant protein A (original) (raw)
Related papers
1997
Sepsis is the most common factor leading to the acute respiratory distress syndrome (ARDS) and is associated with the highest mortality rate. It has been suggested that the pulmonary surfactant system is altered and contributes to the lung dysfunction associated with ARDS. The objective of this study was to characterize the lung injury, specifically the endogenous surfactant system in septic adult rats. Sepsis was induced in male Sprague-Dawley rats by cecal ligation and perforation and resulted in significant increases in heart rates, respiratory rates, and lactate levels along with positive blood cultures in septic animals compared with a sham control group. Two distinct septic groups were developed, a septic group and a sepsis with lung injury (septic � LI) group. The septic group had no significant differences in oxygenation compared with the sham group, whereas the septic � LI group had significantly lower PaO2 and higher A-a gradient values compared to both the sham and septic...
Alterations of the Endogenous Surfactant System in Septic Adult Rats
American Journal of Respiratory and Critical Care Medicine, 1997
Sepsis is the most common factor leading to the acute respiratory distress syndrome (ARDS) and is associated with the highest mortality rate. It has been suggested that the pulmonary surfactant system is altered and contributes to the lung dysfunction associated with ARDS. The objective of this study was to characterize the lung injury, specifically the endogenous surfactant system in septic adult rats. Sepsis was induced in male Sprague-Dawley rats by cecal ligation and perforation and resulted in significant increases in heart rates, respiratory rates, and lactate levels along with positive blood cultures in septic animals compared with a sham control group. Two distinct septic groups were developed, a septic group and a sepsis with lung injury (septic ϩ LI) group. The septic group had no significant differences in oxygenation compared with the sham group, whereas the septic ϩ LI group had significantly lower Pa O 2 and higher A-a gradient values compared to both the sham and septic groups. The total surfactant pool size was significantly lower in the septic ϩ LI group compared with the sham group. The small surfactant aggregate to large surfactant aggregate ratio was significantly lower in the septic group and was further reduced in the septic ϩ LI group. There were also significantly higher levels of surfactant protein A (SP-A) in both septic and septic ϩ LI groups compared to the sham group. These results demonstrated that the endogenous surfactant system was altered in systemic sepsis without lung dysfunction and is further altered when a lung injury is present.
2001
This study examines the relationships between inflammation, surfactant protein (SP) expression, surfactant function, and lung physiology in a murine model of acute lung injury (ALI). 129/J mice received aerosolized endotoxin lipopolysaccharide [LPS] daily for up to 96 h to simulate the cytokine release and acute inflammation of ALI. Lung elastance (E L ) and resistance, lavage fluid cell counts, cytokine levels, phospholipid and protein content, and surfactant function were measured. Lavage and lung tissue SP content were determined by Western blot and immunohistochemistry, and tissue messenger RNA (mRNA) levels were assessed by Northern blot and in situ hybridization. Tumor necrosis factor-␣ and neutrophil counts in bronchoalveolar lavage fluid increased within 2 h of LPS exposure, followed by increases in total protein, interleukin (IL)-1  , IL-6, and interferon-␥ . E L increased within 24 h of LPS exposure and remained abnormal up to 96 h. SP-B protein and mRNA levels were decreased at 24, 48, and 96 h. By contrast, SP-A protein and mRNA levels and SP-C mRNA levels were not reduced. Surfactant dysfunction occurred coincident with changes in SP-B levels. This study demonstrates that lung dysfunction in mice with LPS-ALI corresponds closely with abnormal surfactant function and reduced SP-B expression.
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.
Journal of Applied Physiology, 2001
Mechanical ventilation of isolated septic rat lungs: effects on surfactant and inflammatory cytokines. J Appl Physiol 91: 811-820, 2001.-The effects of mechanical ventilation (MV) on the surfactant system and cytokine secretion were studied in isolated septic rat lungs. At 23 h after sham surgery or induction of sepsis by cecal ligation and perforation (CLP), lungs were excised and randomized to one of three groups: 1) a nonventilated group, 2) a group subjected to 1 h of noninjurious MV (tidal volume ϭ 10 ml/kg, positive end-expiratory pressure ϭ 3 cmH 2O), or 3) a group subjected to 1 h of injurious MV (tidal volume ϭ 20 ml/kg, positive end-expiratory pressure ϭ 0 cmH 2O). Nonventilated sham and CLP lungs had similar compliance, normal lung morphology, surfactant, and cytokine concentrations. Injurious ventilation decreased compliance, altered surfactant, increased cytokines, and induced morphological changes compared with nonventilation in sham and CLP lungs. In these lungs, the surfactant system was similar in sham and CLP lungs; however, tumor necrosis factor-␣ and interleukin-6 levels were significantly higher in CLP lungs. We conclude that injurious ventilation altered surfactant independent of sepsis and that the CLP lungs were predisposed to the secretion of larger amounts of cytokines because of ventilation.
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...
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.
Effects of mechanical ventilation of isolated mouse lungs on surfactant and inflammatory cytokines
2001
Mechanical ventilation of the lung is an essential but potentially harmful therapeutic intervention for patients with acute respiratory distress syndrome. The objective of the current study was to establish and characterize an isolated mouse lung model to study the harmful effects of mechanical ventilation. Lungs were isolated from BalbC mice and randomized to either a nonventilated group, a conventionally ventilated group (tidal volume 7 mL. kg-1 , 4 cm positive endexpiratory pressure (PEEP)) or an injuriously ventilated group (20 mL. kg-1 , 0 cm PEEP). Lungs were subsequently analysed for lung compliance, morphology, surfactant composition and in¯ammatory cytokines. Injurious ventilation resulted in signi®cant lung dysfunction, which was associated with a signi®cant increase in pulmonary surfactant, and surfactant small aggregates compared to the other two groups. Injurious ventilation also led to a signi®cantly increased concentration of interleukin-6 and tumour necrosis factor-a in the lavage. It was concluded that the injurious effects of mechanical ventilation can effectively be studied in isolated mouse lung, which offers the potential of studying genetically altered animals. It was also concluded that in this model, the lung injury is, in part, mediated by the surfactant system and the release of in¯ammatory mediators.
Pulmonary surfactant synthesis after unilateral lung injury in mice
Journal of Applied Physiology, 2014
Aspiration pneumonitis can lead to alveolar surfactant dysfunction. We employed a murine model of unilateral aspiration to compare surfactant synthesis in the injured (I) and noninjured (NI) contralateral lung. Mice were instilled with hydrochloric acid in the right bronchus and, after 18 h, an intraperitoneal dose of deuterated water was administered as precursor of disaturated phosphatidylcholine (DSPC)-palmitate. Selected bronchoalveolar lavage fluid (BALF) was collected at scheduled time points and lungs were removed. We measured DSPC-palmitate synthesis in lung tissue and secretion in BALF by gas chromatography-isotope ratio mass spectrometry, together with total proteins and myeloperoxidase activity (MPO) by spectrophotometry. BALF total proteins and MPO were significantly increased in the I lungs compared with NI and naïve control lungs. The DSPC pool size was significantly lower in the BALF of the I lungs compared with naïve controls. DSPC synthesis was accelerated in the I ...
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...