Inhaled hydrogen sulfide induces suspended animation, but does not alter the inflammatory response after blunt chest trauma

The treatment of acute lung injury and septic complications after blunt chest trauma remains a challenge. Inhaled hydrogen sulfide (H?S) may cause a hibernation-like metabolic state, which refers to an attenuated systemic inflammatory response. Therefore, we tested the hypothesis that inhaled H?S-induced suspended animation may attenuate the inflammation after pulmonary contusion. Male Sprague-Dawley rats were subjected to blunt chest trauma (blast wave) or sham procedure and subsequently exposed to a continuous flow of H?S (100 ppm) or control gas for 6 h. Body temperature and activity were measured by an implanted transmitter. At 6, 24, or 48 h after trauma, animals were killed, and the cellular contents of bronchoalveolar lavage (BAL) as well as cytokine concentrations in BAL, plasma, and culture supernatants of blood mononuclear cells, Kupffer cells, splenic macrophages, and splenocytes were determined. Hydrogen sulfide inhalation caused a significant reduction in body temperature and activity. The trauma-induced increase in alveolar macrophage counts was abrogated 48 h after trauma when animals received H?S, whereas the trauma-induced increase in neutrophil counts was unaltered. Furthermore, H?S inhalation partially attenuated the mediator release in BAL and culture supernatants of Kupffer cells as well as splenic cells; it altered plasma cytokine concentrations but did not affect the trauma-induced changes in mononuclear cell culture supernatants. These findings indicate that inhaled H?S induced a reduced metabolic expenditure and partially attenuated inflammation after trauma. Nevertheless, in contrast to hypoxic- or pathogen-induced lung injury, H?S treatment appears to have no protective effect after blunt chest trauma.     

Increased IL-10 production and HLA-DR suppression in the lungs of injured patients precede the development of nosocomial pneumonia

The incidence of nosocomial pneumonia (NP) among injured patients is substantial. We hypothesize that traumatic injury induces alterations in local organ effector cell function that may predispose the lungs of injured patients to infection. It is the objective of this study to compare the systemic and alveolar effector cell response to injury and assess the relationship these have to the development of NP. Peripheral blood and bronchoalveolar lavage fluid (BAL) were collected from 10 elective surgery patients (controls) and 16 multitrauma patients at 12, 36, and 60 h post-injury. Systemic and alveolar levels of IL-8 and IL-10 were measured. CD11b expression on peripheral blood neutrophils (PBN) and alveolar neutrophils (AN) and HLA-DR expression on peripheral blood monocytes (PBM) and alveolar macrophages (AM) were measured. Alveolar levels of IL-8 and IL-10 were significantly higher than systemic levels after injury. HLA-DR expression was reduced on both PBM and AM after injury but was lowest on the AM. Six of 16 patients (38%) developed NP (NP+). There were no differences in cytokine levels (IL-8 and IL-10) or effector cell phenotype (CD11b and HLA-DR expression) within the systemic circulation of NP+ and NP- patients. In contrast, NP+ and NP- patients differed significantly in alveolar cytokine levels and alveolar effector cell phenotype. IL-8 was significantly higher in BAL form NP+ patients at all time points after injury. Furthermore, alveolar levels of IL-10 decreased in NP- patients but increased in NP+ patients. In all patients, AM HLA-DR expression was significantly reduced from normal controls 12 h post-injury. In NP-patients, AM HLA-DR expression returned to normal 60 h post-injury, whereas in NP+ patients, expression remained suppressed. These findings identify distinct trends in local organ cytokine production and alterations in effector cell phenotype that precede NP. The persistence of reduced HLA-DR expression amidst increasing levels of IL-10 in NP+ patients suggest that cell-mediated immune function is being suppressed. As such, local organ immunosuppression may be responsible for the development of nosocomial pneumonia in injured patients.     

Pulmonary contusion induces alveolar type 2 epithelial cell apoptosis: role of alveolar macrophages and neutrophils

Alveolar type 2 (AT-2) cell apoptosis is an important mechanism during lung inflammation, lung injury, and regeneration. Blunt chest trauma has been shown to activate inflammatory cells such as alveolar macrophages (AMs) or neutrophils (polymorphonuclear granulocytes [PMNs]), resulting in an inflammatory response. The present study was performed to determine the capacity of different components/cells of the alveolar compartment (AMs, PMNs, or bronchoalveolar lavage [BAL] fluids) to induce apoptosis in AT-2 cells following blunt chest trauma. To study this, male Sprague-Dawley rats were subjected to either sham procedure or blunt chest trauma induced by a single blast wave. Various time points after injury (6 h to 7 d), the lungs were analyzed by immunohistochemistry, for AT-2 cells, or with antibodies directed against caspase 3, caspase 8, Fas, Fas ligand (FasL), BAX, and BCL-2. Bronchoalveolar lavage concentrations of TNF-alpha, IL-1beta, and soluble FasL were determined by enzyme-linked immunosorbent assay. Furthermore, cultures of AT-2 cells isolated from healthy rats were incubated with supernatants of AMs, PMNs, or BAL fluids obtained from either trauma or sham-operated animals in the presence or absence of oxidative stress. Annexin V staining or TUNEL (terminal deoxynucleotidyl transferase) assay was used to detect apoptotic AT-2 cells. Histological evaluation revealed that the total number of AT-2 cells was significantly reduced at 48 h following trauma. Fas, FasL, active caspase 8, and active caspase 3 were markedly up-regulated in AT-2 cells after chest trauma. BAX and BCL-2 did not show any significant changes between sham and trauma. IL-1beta, but not TNF-alpha, levels were markedly increased at 24 h after the injury, and soluble FasL concentrations were significantly enhanced at 6, 12, 24, and 48 h after the insult. Apoptosis of AT-2 cells incubated with supernatants from cultured AMs, isolated at 48 h following chest trauma was markedly increased when compared with shams. In contrast, no apoptosis was induced in AT-2 cells incubated with supernatants of activated PMNs or BAL fluids of traumatized animals. In summary, blunt chest trauma induced apoptosis in AT-2 cells, possibly involving the extrinsic death receptor pathway. Furthermore, mediators released by AMs appeared to be involved in the induction of AT-2 cell apoptosis.     

Alveolar macrophage phagocytosis is enhanced after blunt chest trauma and alters the posttraumatic mediator release

Blunt chest trauma is known to induce a pulmonary invasion of short-lived polymorphonuclear neutrophils and apoptosis of alveolar epithelial type 2 (AT2) cells. Apoptotic cells are removed by alveolar macrophages (AMΦ). We hypothesized that chest trauma alters the phagocytic response of AMΦ as well as the mediator release of AMΦ during phagocytosis. To study this, male Sprague-Dawley rats were subjected to blunt chest trauma. Phagocytosis assays were performed in AMΦ isolated 2 or 24 h after trauma with apoptotic cells or opsonized beads. Phagocytosis of apoptotic AT2 cells by unstimulated AMΦ was significantly increased 2 h after trauma. At 24 h, AMΦ from traumatized animals, stimulated with phorbol-12-myristate-13-acetate, ingested significantly more apoptotic polymorphonuclear neutrophils than AMΦ from sham animals. Alveolar macrophages after trauma released significantly higher levels of tumor necrosis factor α, macrophage inflammatory protein 1α, and cytokine-induced neutrophil chemoattractant 1 when they incorporated latex beads, but significantly lower levels of interleukin 1β and macrophage inflammatory protein 1α when they ingested apoptotic cells. In vivo, phagocytosis of intratracheally instilled latex beads was decreased in traumatized rats. The bronchoalveolar lavage concentrations of the phagocytosis-supporting surfactant proteins A and D after blunt chest trauma were slightly decreased, whereas surfactant protein D mRNA expression in AT2 cells was significantly increased after 2 h. These findings indicate that chest trauma augments the phagocytosis of apoptotic cells by AMΦ. Phagocytosis of opsonized beads enhances and ingestion of apoptotic cells downregulates the immunologic response following lung contusion. Our data emphasize the important role of phagocytosis during posttraumatic inflammation after lung contusion.     

Blunt chest trauma induces delayed splenic immunosuppression

Severe blunt chest trauma is frequently associated with multiple organ failure and sepsis. Posttraumatic immunosuppression seems to play a major role in their development. However, the immunologic alterations following pulmonary contusion are insufficiently elucidated. Specifically, it remains unknown whether immunocompetent cells located distant from the site of the impact are affected. We therefore aimed to characterize the influence of pulmonary contusion on lymphocytes and splenic macrophages. Male C3H/HeN mice (n = 8-10/group) were anesthetized and subjected to trauma or sham procedure. Blunt chest trauma was induced by a blast wave focused on the thorax. Two or 24 h later, splenocytes and splenic macrophages were isolated and stimulated for 48 h. The cytokine release (IFN-gamma, IL-2, IL-3, IL-10, IL-12, IL-18) from splenocytes as well as from splenic macrophages (TNF-alpha, IL-10, IL-12, IL-18) and plasma levels of TNF-alpha and IL-6 were quantified by ELISA. The results indicate that at 2 h after blunt chest trauma, plasma TNF-alpha and IL-6 were markedly increased. At the same time, no differences in splenocyte cytokine production were detectable. However, at 24 h a significantly depressed cytokine release was observed in trauma animals. Furthermore, splenic macrophages showed a significantly decreased production of TNF-alpha, IL-10, and IL-12 at 24 h and markedly increased release of IL-18 at 2 h after trauma. These results indicate that blunt chest trauma causes severe immunodysfunction of lymphocytes and splenic macrophages. Thus, lung contusion as a localized type of trauma causes dysfunction of immunocompetent cell populations, which are located distant from the site of injury.     

Pulmonary contusion causes impairment of macrophage and lymphocyte immune functions and increases mortality associated with a subsequent septic challenge

OBJECTIVE AND DESIGN: Pulmonary contusion is frequently followed by acute respiratory distress syndrome, pneumonia, and sepsis. However, immunologic alterations of circulating and resident immune cell populations contributing to the posttraumatic immunosuppression are poorly understood. We therefore characterized the influence of pulmonary contusion on peripheral blood mononuclear cells, peritoneal macrophages, splenocytes, and splenic macrophages. To address the significance of the immunosuppression associated with lung contusion, we investigated how the consecutive addition of moderate or severe sepsis affected survival after blunt chest trauma. SUBJECTS: Male C3H/HeN mice (n = 10 per group) were anesthetized and subjected to chest trauma or sham procedure. MEASUREMENTS: The cytokine release of cultured peripheral blood mononuclear cells, peritoneal macrophages, splenocytes, and splenic macrophages and plasma levels of tumor necrosis factor-alpha and interleukin-6 from those animals were quantified. Sepsis was induced via cecal ligation and puncture 24 hrs after lung contusion. MAIN RESULTS: Two hours after blunt chest trauma, plasma tumor necrosis factor-alpha and interleukin-6 were markedly increased, as was peripheral blood mononuclear cell cytokine production, lung myeloperoxidase activity, and lung chemokine concentrations. At 24 hrs and, in part, already at 2 hrs, cytokine release from peritoneal macrophages, splenic macrophages, and splenocytes was significantly suppressed. Furthermore, pulmonary contusion when followed by moderate sepsis significantly diminished survival rate when compared with chest trauma or moderate sepsis alone. CONCLUSIONS: These results indicate that pulmonary contusion causes severe immunodysfunction of splenocytes, macrophages, and monocytes in different local compartments and systemically. Moreover, this immunosuppression is associated with an increased susceptibility to infectious complications, which results in a decreased survival rate if blunt chest trauma is followed by a septic insult.     

Role of activated neutrophils in chest trauma-induced septic acute lung injury

More than 50% of severely injured patients have chest trauma. Second insults frequently result in acute lung injury (ALI), with sepsis being the main underlying condition. We aimed to develop a standardized, reproducible, and clinically relevant double-hit mouse model of ALI induced by chest trauma and polymicrobial sepsis and to investigate the pathophysiologic role of activated neutrophils. Lung contusion was applied to C57Bl/6 mice via a focused blast wave. Twenty-four hours later, sepsis was induced by cecal ligation and puncture. For polymorphonuclear leukocyte (PMN) depletion, animals received intravenous injections of PMN-depleting antibody. In response to blunt chest trauma followed by sepsis as well as after sepsis alone, a significant local and systemic inflammatory response with increased cytokine/chemokine levels in lung and plasma was observed. In contrast, lung apoptosis was markedly elevated only after a double hit. Intra-alveolar neutrophils and total bronchoalveolar lavage protein concentrations were markedly increased following isolated chest trauma or the combined insult, but not after sepsis alone. Lung myeloperoxidase activity was enhanced only in response to the double hit accompanied by histological disruption of the alveolar architecture, lung congestion, and marked cellular infiltrates. Neutrophil depletion significantly diminished lung interleukin 1β and interleukin 6 concentrations and reduced the degree of septic ALI. Here we have established a novel and highly reproducible mouse model of chest trauma-induced septic ALI characterizing a clinical relevant double-hit scenario. In particular, the depletion of neutrophils substantially mitigated the extent of lung injury, indicating a pathomechanistic role for neutrophils in chest trauma-induced septic ALI.     

Systemic and pulmonary effector cell function after injury

OBJECTIVE: Traumatic injury initiates a complex inflammatory response that is associated with end-organ dysfunction, immunosuppression, and the development of nosocomial infection. We hypothesize that the lungs of injured patients experience a unique inflammatory response to traumatic injury in which the ability of alveolar effector cells to respond to a bacterial challenge is impaired. DESIGN: Prospective, longitudinal comparative study. SETTING: The surgical intensive care unit of an ACS level I trauma center. PATIENTS: Forty consecutive multiple trauma patients requiring mechanical ventilation. MEASUREMENT: Blood and bronchoalveolar lavage fluid were collected on admission, 24, and 48 hrs postinjury. Interleukin (IL)-6, IL-8, and IL-10 were measured in each sample initially and after lipopolysaccharide stimulation by using an ex vivo model of whole blood and bronchoalveolar lavage fluid cellular contents. Five patients who underwent elective surgery formed a control group. MAIN RESULTS: Systemic and alveolar levels of IL-6, IL-8, and IL-10 increase dramatically after severe injury. Levels of IL-6 and IL-8 in trauma bronchoalveolar lavage fluid are significantly greater than those of the systemic circulation. Whereas whole blood up-regulates production of IL-6 and IL-8 in response to lipopolysaccharide, bronchoalveolar lavage fluid cellular contents do not. In contrast, bronchoalveolar lavage fluid and whole blood from injured patients contain similar amounts of IL-10 and both up-regulate IL-10 production in response to lipopolysaccharide. CONCLUSION: The lungs of injured patients experience a profound proinflammatory response to injury more severe than that of the systemic circulation. Within this setting, the ability of alveolar effector cells to respond to a bacterial challenge is diminished compared with that of systemic cells. As such, alveolar effector cell function after injury seems to be impaired, possibly explaining the high frequency of pulmonary infection among these patients.     

Toll-like receptor 4-dependent responses to lung injury in a murine model of pulmonary contusion

Blunt chest trauma resulting in pulmonary contusion with an accompanying acute inflammatory response is a common but poorly understood injury. We previously demonstrated that toll-like receptor 2 (TLR-2) participates in the inflammatory response to lung injury. We hypothesized that the TLR-4, in an MyD88-dependent manner, may also participate in the response to lung injury. To investigate this, we used a model of pulmonary contusion in the mouse that is similar to that observed clinically in humans and evaluated postinjury lung function, pulmonary neutrophil recruitment, and the systemic innate immune response. Comparisons were made between wild-type mice and mice deficient in TLR-4 or MyD88. We found TLR-4-dependent responses to pulmonary contusion that include hypoxemia, edema, and neutrophil infiltration. Increased expression of IL-6 and chemokine (C-X-C motif) ligand 1 in the bronchoalveolar lavage and serum was also dependent on TLR-4 activation. We further demonstrated that these responses to pulmonary contusion were dependent on MyD88, an adapter protein in the signal transduction pathway mediated by TLRs. These results show that TLRs have a primary role in the response to acute lung injury. Lung inflammation and systemic innate immune responses are dependent on TLR activation by pulmonary contusion.     

The evolution of isolated bilateral lung contusion from blunt chest trauma in rats: cellular and cytokine responses

Lung contusion is the leading cause of death from blunt thoracic trauma in adults, but its mechanistic pathophysiology remains unclear. This study uses a recently developed rat model to investigate the evolution of inflammation and injury in isolated lung contusion. Bilateral lung contusion with minimal cardiac trauma was induced in 54 anesthetized rats by dropping a 0.3-kg hollow cylindrical weight onto a precordial shield (impact energy, 2.45 Joules). Arterial oxygenation, pressure-volume (P-V) mechanics, histology, and levels of erythrocytes, leukocytes, albumin, and inflammatory mediators in bronchoalveolar lavage (BAL) were assessed at 8 min, at 4, 12, 24, and 48 h, and at 7 days after injury. The role of neutrophils in the evolution of inflammatory injury was also specifically studied by depleting these cells with intravenous vinblastine before lung contusion. Arterial oxygenation was severely reduced at 8 min to 24 h postcontusion, but became almost normal by 48 h. Levels of erythrocytes, leukocytes, and albumin in BAL were increased at 相似文献   

Innate immune response to pulmonary contusion: identification of cell type-specific inflammatory responses

Lung injury from pulmonary contusion is a common traumatic injury, predominantly seen after blunt chest trauma, such as in vehicular accidents. The local and systemic inflammatory response to injury includes activation of innate immune receptors, elaboration of a variety of inflammatory mediators, and recruitment of inflammatory cells to the injured lung. Using a mouse model of pulmonary contusion, we had previously shown that innate immune Toll-like receptors 2 and 4 (TLR2 and TLR4) mediate the inflammatory response to lung injury. In this study, we used chimeric mice generated by adoptive bone marrow transfer between TLR2 or TLR4 and wild-type mice. We found that, in the lung, both bone marrow-derived and nonmyeloid cells contribute to TLR-dependent inflammatory responses after injury in a cell type-specific manner. We also show a novel TLR2-dependent injury mechanism that is associated with enhanced airway epithelial cell apoptosis and increased pulmonary FasL and Fas expression in the lungs from injured mice. Thus, in addition to cardiopulmonary physiological dysfunction, cell type-specific TLR and their differential response to injury may provide novel specific targets for management of patients with pulmonary contusion.     

Induction of apoptosis following blunt chest trauma

The cause for the high morbidity of blunt chest trauma is not fully understood. It is still unclear if and to what extent a second insult, e.g., apoptotic tissue damage initiated by the primary insult itself, may contribute to the development of serious complications. This study was done to elucidate whether a pulmonary contusion may induce programmed cell death. Sixty-four Wistar rats were evenly randomized to eight experimental groups: four sets were subjected to a standardized blast wave injury and sacrificed 6, 24, 48, and 72 h after the trauma; four groups served as controls for the same time points. Lung and liver samples were stained (H & E; TUNEL), and PMN infiltration was determined by myeloperoxidase (MPO) activity. Caspase 8 was analyzed by Western blot, and TNF-alpha plasma levels by ELISA. Postmortem examination revealed bilateral pulmonary contusion in trauma animals with higher (P < 0.05) numbers of apoptotic cells in lung but not in liver tissue as early as 6 h after the injury. This amount gradually increased and reached a maximum after 48 h: 6.8 +/- 1.1 apoptotic cells/hpf vs. 0.6 +/- 0.06 in controls. Chest trauma caused an increased expression of active caspase 8 in lung but not in liver tissue at 48 and 72 h. TNF-alpha plasma levels were not different. MPO activity in lung tissue of trauma animals increased (P < 0.05) after 6 h and peaked at 72 h. This study has provided the first evidence that apoptotic cell death in lung tissue is initiated following (experimental) pulmonary contusion. The exact mechanism remains, however, unclear and has to be elucidated further.     

脊髓损伤后组织基因表达谱的变化

目的通过基因芯片全面了解组织损伤后基因表达变化情况,研究脊髓损伤后组织基因表达谱的变化。方法健康成年SD大鼠9只,体质量300～400g,雌雄不拘,随机数字法分为无损伤组及损伤2、48h组,每组3只。以打击法制成大鼠脊髓闭合性损伤的动物模型,利用表达谱基因芯片技术,检测正常及伤后2,48h脊髓组织基因表达谱,寻找伤后发生显著差异性表达的基因。结果有45条基因在脊髓损伤后2h发生了显著差异性表达,其中22条表达升高,23条表达下降;183条基因在伤后48h发生显著变化,包括61条表达升高,122条表达下降。结论脊髓损伤后不同时期,多条基因发生了表达变化,提示继发性脊髓损伤是一个多因素参与的过程。     

Immunoparalysis in patients with severe trauma and the effect of inhaled interferon-gamma

OBJECTIVE: To evaluate the local immune status in patients with severe trauma and the influence of interferon-gamma on patients with immunoparalysis. PATIENTS: Fifty-two mechanically ventilated patients with severe multiple trauma. SETTING: A 14-bed polyvalent intensive care unit. INTERVENTIONS: The local immune status was evaluated by examining bronchoalveolar lavage fluid. Subsequently, the patients were divided into two groups: immunoparalyzed (group 1) and nonimmunoparalyzed (group 2). Immunoparalysis was defined as a decreased level of human leukocyte antigen-DR expression of alveolar macrophages in <30%. Patients with immunoparalysis were treated with 100 microg of inhaled recombinant human interferon-gamma, three times daily (group 1a, 11 patients) or placebo (group 1b, ten patients). A second bronchoalveolar lavage fluid was obtained 3 days after the initiation of therapy. MEASUREMENTS: The alterations in human leukocyte antigen-DR expression, as well as in pro- and anti-inflammatory markers, such as platelet-aggregating factor, phospholipase A2, interleukin-1beta, platelet-aggregating factor acetylhydrolase, and interleukin-10, were evaluated in the bronchoalveolar lavage fluids. RESULTS: In 21 of 52 (40%) patients, immunoparalysis was established. After interferon-gamma administration, the level of human leukocyte antigen-DR expression increased in group 1a from 17 +/- 5% to 46 +/- 9%. In parallel, platelet-aggregating factor and interleukin-1beta as well as the specific activities of phospholipase A2 and platelet-aggregating factor acetylhydrolase significantly increased. In contrast, interleukin-10 decreased after interferon-gamma therapy. In group 1b, no statistically significant changes appeared in the levels of human leukocyte antigen-DR expression or in the concentrations of inflammatory mediators. The incidence of ventilator-associated pneumonia was significantly lower in group 1a than in group 1b. The administration of interferon-gamma did not affect the outcome of the patients. CONCLUSIONS: A significant proportion of multiply injured patients developed immunoparalysis. The administration of interferon-gamma resulted in the recovery of levels of human leukocyte antigen-DR expression in alveolar macrophages, influenced the inflammatory reaction, and decreased the incidence ventilator-associated pneumonia, without affecting the patients' outcome.     

Mechanism of neutrophil recruitment to the lung after pulmonary contusion

Blunt chest trauma resulting in pulmonary contusion is a common but poorly understood injury. We previously demonstrated that lung contusion activates localized and systemic innate immune mechanisms and recruits neutrophils to the injured lung. We hypothesized that the innate immune and inflammatory activation of neutrophils may figure prominently in the response to lung injury. To investigate this, we used a model of pulmonary contusion in the mouse that is similar to that observed clinically in humans and evaluated postinjury lung function and pulmonary neutrophil recruitment. Comparisons were made between injured mice with and without neutrophil depletion. We further examined the role of chemokines and adhesion receptors in neutrophil recruitment to the injured lung. We found that lung injury and resultant physiological dysfunction after contusion were dependent on the presence of neutrophils in the alveolar space. We show that CXCL1, CXCL2/3, and CXCR2 are involved in neutrophil recruitment to the lung after injury and that intercellular adhesion molecule 1 is locally expressed and actively participates in this process. Injured gp91-deficient mice showed improved lung function, indicating that oxidant production by neutrophil NADPH oxidase mediates lung dysfunction after contusion. These data suggest that both neutrophil presence and function are required for lung injury after lung contusion.     

Dysfunction of alveolar macrophages after cardiac surgery and postoperative pneumonia? - an observational study

Introduction

Patients undergoing cardiac surgery have an increased risk of postoperative pneumonia. Pulmonary immune dysfunction might be a contributing factor. We therefore determined changes of the surface molecules on alveolar macrophages (AMs). To characterize modulation in patients with pneumonia we correlated these changes to the development of postoperative pneumonia.

Methods

After ethical approval and written informed consent, 33 patients undergoing elective coronary bypass grafting surgery were included in this observational study. Peripheral blood cells and alveolar lavage fluid were collected directly after induction of anesthesia and two hours after separation from cardiopulmonary bypass (CPB). Human leukocyte antigen-DR (HLA-DR) and toll-like receptors (TLR) 2/4 expression on monocytes and AM were assessed by flow cytometry. A total of three patients developed postoperative pneumonia determined according to the criteria of the Center of Disease Control. Statistical analysis was performed with the Mann–Whitney-U test and Wilcoxon test.

Results

We found significant changes of phenotypic and functional immune markers on AMs after cardiac surgery. HLA-DR expression on peripheral blood monocytes and AMs was significantly reduced compared to baseline in all patients (each approximately 30%). After surgery patients who developed postoperative pneumonia revealed a trend of stronger reduction of HLA-DR expression (83.7% versus 27.1%) and TLR4 expression on AMs (46.1% versus 9.9%) compared to patients without pneumonia. Already before surgery, the baseline of TLR2 expression on AM was significantly lower (27.7%) in patients who developed postoperative pneumonia.

Conclusions

As far as we know this is the first study that shows an early impairment of lung cellular immune response after cardiac surgery. These findings can help to understand the role of cell-mediated immunosuppression and its association to the development of postoperative pneumonia.     

Distribution and function of alveolar cells in multiply injured patients with trauma-induced ARDS

To determine whether alveolar cells are involved in the pathogenesis of adult respiratory distress syndrome (ARDS), we assessed the distribution and function of alveolar cells from 30 polytraumatized patients with trauma-induced respiratory failure, 5 of whom also had lung contusion. Cells were obtained by bronchoalveolar lavage performed daily begining on the day of trauma and continuing for 14 days. Neutrophils constituted about 60% of lavage cells in ARDS patients with lung contusion 0–2 days after polytrauma and about 50% in ARDS patients without lung contusion. In ARDS patients with lung contusion the neutrophil fraction decreased to 52% 3–6 days after trauma and to 40% 7–14 days after trauma. In patients without lung contusion the neutrophil fraction increased to 77% and then decreased to 60% at these times. Total cell counts in ARDS patients with lung contusion were more than twice as high as in patients without lung contusion 0–2 days after trauma. The difference in total cell counts decreased during days 3–6 and disappeared by day 7. In all patients morphologically altered alveolar cells were observed 4 days and more after trauma. In non-survivors significantly more altered cells were found. The chemiluminescence-response pattern of the alveolar cells was enhanced throughout the study and correlated with the neutrophil fraction (r=0.6). The neutrophil fraction also correlated with the pulmonary vascular resistance during the first two days after trauma (r=0.53). We conclude that alveolar cells are involved in the pathogenesis of trauma-induced ARDS and that the alveolar cell distribution is different in patients with and without lung contusion during the development of posttraumatic respiratory failure.Part of this paper was presented as a poster at the VII^th International Symposium on Intensive Care and Emergency Medicine, Brussels, Belgium, March 1987     

Inhaled aerosolized insulin ameliorates hyperglycemia-induced inflammatory responses in the lungs in an experimental model of acute lung injury

Introduction

Previous studies have shown that patients with diabetes mellitus appear to have a lower prevalence of acute lung injury. We assumed that insulin prescribed to patients with diabetes has an anti-inflammatory property and pulmonary administration of insulin might exert beneficial effects much more than intravenous administration.

Methods

Twenty-eight mechanically ventilated rabbits underwent lung injury by saline lavage, and then the animals were allocated into a normoglycemia group (NG), a hyperglycemia group (HG), an HG treated with intravenous insulin (HG-VI) group or an HG treated with aerosolized insulin (HG-AI) group with continuous infusion of different fluid solutions and treatments: normal saline, 50% glucose, 50% glucose with intravenous insulin, or 50% glucose with inhaled aerosolized insulin, respectively. After four hours of treatment, the lungs and heart were excised en bloc, and then high-mobility group B1 concentration in bronchoalveolar lavage fluid, interleukin-8 and toll-like receptor 4 mRNA expression in bronchoalveolar lavage fluid cells, and lung myeloperoxidase activity were measured.

Results

Treatment with both aerosolized insulin and intravenous insulin attenuated toll-like receptor 4 mRNA expressions in the bronchoalveolar lavage fluid cells. Interleukin-8 and toll-like receptor 4 mRNA expression was significantly lower in the HG-AI group than in the HG-IV group. The lung myeloperoxidase activity in the normal healthy group showed significantly lower levels compared to the NG group but not different compared to those of the HG, HG-VI and HG-AI groups.

Conclusions

The results suggest that insulin attenuates inflammatory responses in the lungs augmented by hyperglycemia in acute lung injury and the insulin''s efficacy may be better when administered by aerosol.     

Alpha-1-antitrypsin content in the serum, alveolar macrophages, and alveolar lavage fluid of smoking and nonsmoking normal subjects.

The content of alpha-1-antitrypsin in the serum, alveolar lavage fluid, and alveolar macrophages of smokers and nonsmokers was studied. Bronchoalveolar lavage was used to obtain alveolar fluid and macrophages from normal volunteers, and alpha-1-antitrypsin and albumin were measured using the electroimmunodiffusion technique. The serum level of inhibitor was not different between the two groups, while the total lavage fliud content of alpha-1-antitrypsin was increased in the smokers. The level of alpha-1-antitrypsin was also significantly greater (P less than 0.001) in the alveolar macrophages of the smokers suggesting the possibility of chronically increased alveolar levels in the cigarette smoker as a possible protective mechanism against proteolysis.