Uninjured Lungs Research Articles

Physiologic assessment of the ex vivo donor lung for transplantation

The evaluation of donor lungs by normothermic ex vivo acellular perfusion has improved the safety of organ utilization. However, this strategy requires a critical re-evaluation of the parameters used to assess lungs during ex vivo perfusion compared with those traditionally used to evaluate the donor lung in vivo. Using a porcine model, we studied the physiology of acellular lung perfusion with the aim of improving the accuracy of clinical ex vivo evaluation. Porcine lungs after 10 hours of brain death and 24 hours of cold ischemia and uninjured control lungs were perfused for 12 hours and then transplanted. PaO2, compliance, airway pressure and pulmonary vascular resistance were measured. Ventilation with 100% nitrogen and addition of red blood cells to the perfusate were used to clarify the physiologic disparities between in vivo blood perfusion and ex vivo acellular perfusion. During 12 hours of ex vivo perfusion, injured lungs developed edema with decreased compliance and increased airway pressure, but ex vivo PO2 remained stable. After transplantation, injured lungs demonstrated high vascular resistance and poor PaO2. A reduced effect of shunt on ex vivo lung perfusion PO2 was found to be attributable to the linearization of the relationship between oxygen content and PO2, which occurs with acellular perfusate. Ex vivo PO2 may not be the first indication of lung injury and, taken alone, may be misleading in assessing the ex vivo lung. Thus, evaluation of other physiologic parameters takes on greater importance.

Tidal Volumes during General Anesthesia

Tidal Volumes during General Anesthesia

Exhaled Breath Condensate in Mechanically Ventilated Brain-injured Patients with No Lung Injury or Sepsis

The inflammatory influence of prolonged mechanical ventilation in uninjured lungs remains a matter of controversy and largely unexplored in humans. The authors investigated pulmonary inflammation by using exhaled breath condensate (EBC) in mechanically ventilated, brain-injured patients in the absence of acute lung injury or sepsis and explored the potential influence of positive end-expiratory pressure (PEEP). Inflammatory EBC markers were assessed in 27 mechanically ventilated, brain-injured patients with neither acute lung injury nor sepsis and in 12 healthy and 8 brain-injured control subjects. Patients were ventilated with 8 ml/kg during zero end-expiratory pressure (ZEEP group, n = 12) or 8 cm H(2)O PEEP (PEEP group, n = 15). EBC was collected on days 1, 3, and 5 of mechanical ventilation to measure pH; interleukins (IL)-10, 1β, 6, 8, and 12p70; and tumor necrosis factor-α. EBC pH was lower, whereas IL-1β and tumor necrosis factor-α were greater in both patient groups compared with either control group; IL-6 was higher, whereas IL-10 and IL-12p70 were sporadically higher than in healthy control subjects; no differences were noted between the two patient groups, except for IL-10, which decreased by day 5 during PEEP. Leukocytes, soluble IL-6, and soluble triggering receptor expressed on myeloid cells-1 in blood were constantly higher during zero end-expiratory pressure; EBC cytokines appeared mostly related to soluble IL-8 and inversely related to soluble triggering receptor expressed on myeloid cells-1. In brain-injured, mechanically ventilated patients with neither acute lung injury nor sepsis, EBC markers appear to indicate the presence of subtle pulmonary inflammation that is mostly unaffected by PEEP. There is evidence for a systemic inflammatory response, especially in patients during zero end-expiratory pressure.

Pretreatment with perfluorohexane vapor attenuates fMLP-induced lung injury in isolated perfused rabbit lungs

ABSTRACTThe authors investigated the protective effects and dose dependency of perfluorohexane (PFH) vapor on leukocyte-mediated lung injury in isolated, perfused, and ventilated rabbit lungs. Lungs received either 18 vol.% (n = 7), 9 vol.% (n = 7), or 4.5 vol.% (n = 7) PFH. Fifteen minutes after beginning of PFH application, lung injury was induced with formyl-Met-Leu-Phe (fMLP). Control lungs (n = 7) received fMLP only. In addition 5 lungs (PFH-sham) remained uninjured receiving 18 vol.% PFH only. Pulmonary artery pressure (mPAP), peak inspiratory pressure (Pmax), and lung weight were monitored for 90 minutes. Perfusate samples were taken at regular intervals for analysis and representative lungs were fixed for histological analysis. In the control, fMLP application led to a significant increase of mPAP, Pmax, lung weight, and lipid mediators. Pretreatment with PFH attenuated the rise in these parameters. This was accompanied by preservation of the structural integrity of the alveolar architecture and air-blood barrier. In uninjured lungs, mPAP, Pmax, lung weight, and lipid mediator formation remained uneffected in the presence of PFH. The authors concluded that pretreatment with PFH vapor leads to an attenuation of leukocyte-mediated lung injury. Vaporization of perfluorocarbons (PFCs) offers new therapeutic options, making use of their protective and anti-inflammatory properties in prophylaxis or in early treatment of acute lung injury.

Protective ventilation therapy

General anesthesia and mechanical ventilation affect gas exchange, ventilation and pulmonary perfusion and there is an increasing body of evidence that mechanical ventilation itself promotes lung injury. Lung protective mechanical ventilation in patients suffering from acute lung injury or acute respiratory distress syndrome by means of reduced tidal volumes and limited plateau pressures has been shown to result in reduction of systemic inflammatory mediators, increased ventilator-free days and reduction in mortality. Experimental studies suggest that mechanical ventilation of uninjured lungs may also induce lung damage; however, the clinical relevance remains unknown. Human prospective studies comparing mechanical ventilation strategies during general anesthesia have shown inconsistent results with respect to inflammatory mediators. There is a lack of clinical evidence that lung protective ventilation strategies as used in patients with lung injury may improve clinical outcome of patients with uninjured lungs. The question of which ventilatory strategy will best protect normal human lungs remains unanswered.

Spatial distribution of sequential ventilation during mechanical ventilation of the uninjured lung: an argument for cyclical airway collapse and expansion

BackgroundVentilator-induced lung injury (VILI) is a recognized complication of mechanical ventilation. Although the specific mechanism by which mechanical ventilation causes lung injury remains an active area of study, the application of positive end expiratory pressure (PEEP) reduces its severity. We have previously reported that VILI is spatially heterogeneous with the most severe injury in the dorsal-caudal lung. This regional injury heterogeneity was abolished by the application of PEEP = 8 cm H2O. We hypothesized that the spatial distribution of lung injury correlates with areas in which cyclical airway collapse and recruitment occurs.MethodsTo test this hypothesis, rabbits were mechanically ventilated in the supine posture, and regional ventilation distribution was measured under four conditions: tidal volumes (VT) of 6 and 12 ml/kg with PEEP levels of 0 and 8 cm H2O.ResultsWe found that relative ventilation was sequentially redistributed towards dorsal-caudal lung with increasing tidal volume. This sequential ventilation redistribution was abolished with the addition of PEEP.ConclusionsThese results suggest that cyclical airway collapse and recruitment is regionally heterogeneous and spatially correlated with areas most susceptible to VILI.

Effects of perfluorohexane vapor in the treatment of experimental lung injury

Rationale We investigated the effects of vaporized perfluorohexane (PFH) on pulmonary vascular tone, pulmonary vascular resistance and peak inspiratory pressure as well as lipid mediator formation in the treatment of calcium ionophore induced lung injury in a model of the isolated perfused and ventilated rabbit lungs. Methods Lung injury was induced in isolated perfused and ventilated rabbit lungs by calcium ionophore A23187. Lungs were treated with either 4.5 vol.% (4.5 vol.% PFH; n = 6) or 18 vol.% (18 vol.% PFH; n = 6) PFH. Six lungs remained untreated (Control). In addition 5 lungs (PFH-sham) remained uninjured receiving 18 vol.% PFH only. Mean pulmonary artery pressure (mPAP), peak inspiratory pressure ( P max), and lung weight (weight) were monitored for 120 min. Experiments were terminated before when the increase in lung weight exceeded 40 g. Perfusate samples were taken at regular intervals for analysis of TXB 2, 6-keto-PGF 1 and LTB 4. Results Controls reached the study end point significantly earlier than both PFH groups. Significant differences were found for a weight gain of 10 g and 20 g between the control and the 4.5 vol.% PFH and the 18 vol.% PFH. Differences in mPAP were more pronounced in the 4.5 vol.% PFH. However increases in P max were more marked in 4.5 vol.% PFH. TXA 2-, PGI 2-, and LTB 4-levels were significantly lower in PFH groups. Uninjured lungs remained unaffected by the presence of 18 vol.% PFH. Conclusion Inflammatory lung injury was attenuated by the treatment with 4.5 vol.% PFH and 18 vol.% PFH vapor in the isolated perfused rabbit lung. Therapeutic effects were more pronounced with a concentration of 4.5 vol.% PFH.

How Much PEEP in Acute Lung Injury

ACUTE LUNG INJURY (ALI) IS A COMMON, LETHAL, AND complex syndrome. Estimates of attributable mortality from ALI or its more severe form, acute respiratory distress syndrome (ARDS), in the United States place it above asthma and human immunodeficiency virus infection as a cause of death. The current mortality of 35% associated with ALI is roughly 3-fold higher than that associated with ST-segment elevation myocardial infarction. Most of the salient features of ARDS, including the therapeutic use of positive end-expiratory pressure (PEEP), were described by Ashbaugh et al in their classic description of the syndrome: “ventilation without positive end-expiratory pressure resulted in immediate hypoxaemia. . . . Collapsed alveoli require greater pressures for reopening, thus explaining the notable loss of compliance. Positive end-expiratory pressure would theoretically prevent complete collapse and improve oxygenation by maintaining alveolar ventilation.” Ashbaugh et al thought that mechanical ventilation merely prevented hypoxemic death, thereby providing clinicians with time to treat the underlying cause of ARDS. However, recent research has focused on the degree to which mechanical ventilation is injurious, depending on how it is applied, by causing inflammation and multiple organ failure. There is little disagreement about the principles of mechanical ventilation in patients with ALI: a PEEP sufficient to recruit collapsed lung areas should be used while delivering small tidal volumes to protect the uninjured lung from overdistention. These basic concepts do not provide any of the details required to manage the care of patients at the bedside. Although the use of PEEP is a simple physiological intervention, it has potentially deleterious effects on right and left ventricular function, pulmonary vascular resistance, and thoracic compliance, leading to unpredictable effects on gas exchange and hemodynamics in individual patients. Airway pressures necessary to recruit collapsed lung areas can improve oxygenation but also can overdistend normal areas of pulmonary parenchyma, worsen inflammation, and reduce cardiac output. Therefore, identifying the optimal PEEP to use in ALI has been the focus of a substantial amount of clinical investigation. Many strategies exist: clinicians can increase PEEP to achieve the maximal improvement in oxygenation, sacrificing overdistention of normal alveoli; balance oxygenation benefits against cardiac output or blood pressure; use pressure-volume curves or dynamic stress indices to identify a trade-off point of lung recruitment; or use sophisticated imaging techniques to assess how much lung has been opened. However, in clinical practice, patients with ALI do not appear to benefit from any of these strategies. Large cohorts of patients receiving mechanical ventilation show that patients with ALI, ARDS, acute respiratory failure that is neither ALI nor ARDS, and patients with chronic obstructive pulmonary disease all receive, on average, about 8 cm H2O of PEEP. Current practice may reflect the lack of evidence demonstrating a patient-centered outcome benefit of any specific approach to titrating PEEP. Four recent clinical trials address the question of “How much PEEP in acute lung injury?”: ALVEOLI, LOVS, EXPRESS, and EPVENT. All of these investigations were designed to measure the benefits of a protocolized higher PEEP strategy in a broad range of patients with ALI receiving tidal volumes thought to be protective. The protocols tested were related only in that they delivered approximately 14.5 to 18 cm H2O of PEEP on day 1 to patients in the intervention groups. The usual set of explanations were invoked to interpret the results of high-quality, wellconceived, but statistically negative trials; ie, the wrong patients were enrolled; too few patients were enrolled because of overly optimistic projections of the effect of PEEP on mortality; and unlucky randomization led to sicker patients in the intervention groups and to investigators not using the right approach to setting PEEP. In this issue of JAMA, a meta-analysis of individualpatient data by Briel and colleagues addresses 3 of these 4 important limitations. Using primary data from the actual trials, the authors demonstrated that, after adjusting for individual patient covariates, higher PEEP was associated with

Analysis of Adeno-associated Virus Progenitor Cell Transduction in Mouse Lung

Although recombinant adeno-associated virus (rAAV) has been widely used in lung gene therapy approaches, it remains unclear to what extent commonly used AAV serotypes transduce adult progenitors in the lung. In this study, we evaluated the life span and proliferative capacity of rAAV1-, 2-, and 5-transduced airway cells in mouse lung, using a LacZ-CRE reporter transgenic model and Cre-expressing rAAV. In this model, the expression of CRE recombinase led to permanent genetic marking of transduced cells and their descendants with LacZ. To investigate whether the rAAV-transduced cells included airway progenitors, we injured the airways of rAAV-infected mice with Naphthalene, while simultaneously labeling with 5-bromodeoxyuridine (BrdU) to identify slow-cycling progenitor/stem cells that entered the cell cycle and retained label. Both rAAV5 and rAAV1 vectors were capable of transducing a subset of long-lived Clara cells and alveolar type II (ATII) cells that retained nucleotide label and proliferated following lung injury. Importantly, rAAV1 and 5 appeared to preferentially transduce conducting airway epithelial progenitors that had the capacity to clonally expand, both in culture and in vivo following lung injury. These studies suggest that rAAV may be a useful vector for gene targeting of airway stem/progenitor cells.

PULMONARY EXPRESSION OF NITRIC OXIDE SYNTHASE ISOFORMS IN SHEEP WITH SMOKE INHALATION AND BURN INJURY

Previous studies have indicated increased plasma levels of inducible nitric oxide synthase in lung. This study further examines the pulmonary expression of nitric oxide synthase (NOS) isoforms in an ovine model of acute lung injury induced by smoke inhalation and burn injury (S+B injury). Female range bred sheep (4 per group) were sacrificed at 4, 8, 12, 24, and 48 hours after injury and immunohistochemistry was performed in tissues for various NOS isoforms. The study indicates that in uninjured sheep lung, endothelial (eNOS) is constitutively expressed in the endothelial cells associated with the airways and parenchyma, and in macrophages. Similarly, neuronal (nNOS) is constitutively present in the mucous cells of the epithelium and in neurons of airway ganglia. In uninjured lung, inducible (iNOS) was present in bronchial secretory cells and macrophages. In tissue after S+B injury, new expression of iNOS was evident in bronchial ciliated cells, basal cells, and mucus gland cells. In the parenchyma, a slight increase in iNOS immunostaining was seen in type I cells at 12 and 24 hours after injury only. Virtually no change in eNOS or nNOS was seen after injury.

Reply to Fisher and Beers: Animal models of acute lung injury

reply: We thank Drs. Fisher and Beers (3) for their comments, which support the key statements made in the hyperoxia section of our manuscript (6), namely that there is no conclusive evidence (level A or B) showing that, in humans, exposure to 100% oxygen under normobaric conditions results in acute lung injury/acute respiratory distress syndrome (ALI/ARDS); that, in contrast, in most animal studies, exposure to 100% oxygen consistently results in lethal lung injury; and that, therefore, there are important differences in susceptibility to oxygen in humans and other mammalian species. We did not intend to imply that hyperoxia is harmless in humans or that clinicians should not pay attention to the FiO2 in ventilated patients. We are simply highlighting the fact that although exposure of normal animals to 100% oxygen under normobaric conditions reproducibly causes lung injury, the same is not true in humans, and therefore caution should be used when extrapolating findings from the hyperoxic model to humans, particularly when investigating putative causes of ALI/ARDS in previously uninjured lungs. However, as we discuss in the review, the hyperoxic animal model has many advantages, including reproducibility, and it remains an excellent model in which to study lung repair or the contributions of hyperoxia to preexisting lung injury. Furthermore, the hyperoxia model appears to be more physiological than other ALI models such as intratracheal bleomycin. As Fisher and Beers (3) point out, our statements about hyperoxia and human ALI/ARDS are partly based on a study by Barber and Hamilton (1) in which patients with brain injury were exposed to 100% oxygen but failed to develop ALI. We believe that this negative study is important because it clearly demonstrates that normobaric hyperoxia is not necessarily followed by lung injury in humans. The Kapanci et al. (5) paper that according to Fisher and Beers (3) “demonstrated significant lung injury” in response to oxygen is more difficult to interpret because other factors now known to be associated with lung injury, such as the tidal volume, were not reported. For the same reasons, it is difficult to conclude that Hyde and Rawson's study (4) demonstrated that “exposure of patients with normal lungs to prolonged hyperoxia resulted in clinical findings compatible with oxygen toxicity.” The single patient who died in that study was found disconnected from the ventilator, making it unclear as to whether his death was truly “pulmonary-related.” As mentioned by Fisher and Beers (3), humans exposed to normobaric hyperoxia develop tracheobronchitis and mild changes in permeability but not ALI (2). Thus the existing literature does not show that exposure of humans to 100% oxygen under normobaric conditions results in ALI/ARDS. We agree with Fisher and Beers (3) that the difference in oxygen susceptibility seen in humans and other mammalian species likely reflects inheritable variability at the genetic level, and it remains possible that subgroups of people exist who have increased susceptibility to oxygen-induced lung injury. Thus we do not believe that our published paper has “misleading and potentially dangerous statements concerning the role of hyperoxia in human acute lung injury.” Although we agree that “diligence is necessary when humans are exposed to elevated partial pressures of O2,” we also believe that it is important to be cautious when clinical decisions are based on data generated primarily from animal studies.

Alveolar recruitment can be predicted from airway pressure-lung volume loops: an experimental study in a porcine acute lung injury model

IntroductionSimple methods to predict the effect of lung recruitment maneuvers (LRMs) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are lacking. It has previously been found that a static pressure–volume (PV) loop could indicate the increase in lung volume induced by positive end-expiratory pressure (PEEP) in ARDS. The purpose of this study was to test the hypothesis that in ALI (1) the difference in lung volume (ΔV) at a specific airway pressure (10 cmH2O was chosen in this test) obtained from the limbs of a PV loop agree with the increase in end-expiratory lung volume (ΔEELV) by an LRM at a specific PEEP (10 cmH2O), and (2) the maximal relative vertical (volume) difference between the limbs (maximal hysteresis/total lung capacity (MH/TLC)) could predict the changes in respiratory compliance (Crs), EELV and partial pressures of arterial O2 and CO2 (PaO2 and PaCO2, respectively) by an LRM.MethodsIn eight ventilated pigs PV loops were obtained (1) before lung injury, (2) after lung injury induced by lung lavage, and (3) after additional injurious ventilation. ΔV and MH/TLC were determined from the PV loops. At all stages Crs, EELV, PaCO2 and PaO2 were registered at 0 cmH2O and at 10 cmH2O before and after LRM, and ΔEELV was calculated. Statistics: Wilcoxon's signed rank, Pearson's product moment correlation, Bland–Altman plot, and receiver operating characteristics curve. Medians and 25th and 75th centiles are reported.ResultsΔV was 270 (220, 320) ml and ΔEELV was 227 (177, 306) ml (P < 0.047). The bias was 39 ml and the limits of agreement were – 49 ml to +127 ml. The R2 for relative changes in EELV, Crs, PaCO2 and PaO2 against MH/TLC were 0.55, 0.57, 0.36 and 0.05, respectively. The sensitivity and specificity for MH/TLC of 0.3 to predict improvement (>75th centile of what was found in uninjured lungs) were for EELV 1.0 and 0.85, Crs 0.88 and 1.0, PaCO2 0.78 and 0.60, and PaO2 1.0 and 0.69.ConclusionA PV-loop-derived parameter, MH/TLC of 0.3, predicted changes in lung mechanics better than changes in gas exchange in this lung injury model.

Hematopoietic Progenitor Cells Mobilize to the Site of Injury After Trauma and Hemorrhagic Shock in Rats

Trauma and hemorrhagic shock (T/HS) has been demonstrated to result in bone marrow (BM) suppression and the release of hematopoietic progenitor cells (HPC) into the peripheral blood in both human beings and experimental animals. HPC have also been identified in numerous end organs after T/HS and the ongoing loss of progenitor cells from the BM may play a role in posttraumatic BM suppression. We investigated the hypothesis that HPC will specifically migrate to sites of tissue trauma and that this process is exacerbated by hemorrhagic shock (HS). Sprague-Dawley rats (250-400 g) sustaining a unilateral lung contusion (LC) secondary to a blast wave of a percussive nail gun, were subjected to either HS (MAP 40-45 mm Hg for 45 minutes) or sham shock (SS). Animals were killed at 3 hours, 3 days, and 7 days after resuscitation and the right and left lungs from each animal were processed separately and the uninjured left lung served as a control for comparison with the contused right lung. BM mononuclear cells from each individual lung and the femurs were isolated and plated (2 x 10) in duplicate for granulocyte-macrophage colony-forming units (CFU-GM), erythroid colony-forming units (CFU-E), and erythroid burst-forming units (BFU-E) colony growth. At 3 hours, LC resulted in a significant increase in progenitor colonies able to be grown from the injured lung compared with from the uninjured lung (CFU-GM: 11 +/- 1 vs. 5 +/- 2, CFU-E: 12 +/- 7 vs. 5 +/- 3, BFU-E: 7 +/- 1 vs. 3 +/- 1 colonies per 10 BM mononuclear cells; all p < 0.05). HS resulted in a significant increase of the number of colonies of all three cell types in both the uninjured and the contused lung (all p < 0.05). At day 3 after HS, BM progenitor growth remained suppressed whereas the number of cells recoverable from the lung returned toward baseline. By day 7, hematopoietic progenitor cell growth in the BM and the number of those cells able to be grown from the lung returned to levels observed in unmanipulated rats. Unilateral LC results in the rapid mobilization of a significant number of HPC from the BM to the site of injury. BM function is maintained under this condition. The addition of HS increases HPC mobilization from the BM and sequestration at the site of injury as well as decreasing BM HPC growth. We postulate that the accumulation of progenitor cells in the injured tissue combined with an alteration of normal BM homing, as exemplified by the decrease in progenitor cells from the lung without restoration of BM function, plays a role in posttraumatic BM suppression. The mechanism of shock-mediated mobilization from the BM and the exact role and fate of these cells at the site of injury requires further investigation.

Airway strain during mechanical ventilation in an intact animal model.

Mechanical ventilation with large tidal volumes causes ventilator-induced lung injury in animal models. Little direct evidence exists regarding the deformation of airways in vivo during mechanical ventilation, or in the presence of positive end-expiratory pressure (PEEP). To measure airway strain and to estimate airway wall tension during mechanical ventilation in an intact animal model. Sprague-Dawley rats were anesthetized and mechanically ventilated with tidal volumes of 6, 12, and 25 cm(3)/kg with and without 10-cm H(2)O PEEP. Real-time tantalum bronchograms were obtained for each condition, using microfocal X-ray imaging. Images were used to calculate circumferential and longitudinal airway strains, and on the basis of a simplified mathematical model we estimated airway wall tensions. Circumferential and longitudinal airway strains increased with increasing tidal volume. Levels of mechanical strain were heterogeneous throughout the bronchial tree. Circumferential strains were higher in smaller airways (less than 800 mum). Airway size did not influence longitudinal strain. When PEEP was applied, wall tensions increased more rapidly than did strain levels, suggesting that a "strain limit" had been reached. Airway collapse was not observed under any experimental condition. Mechanical ventilation results in significant airway mechanical strain that is heterogeneously distributed in the uninjured lung. The magnitude of circumferential but not axial strain varies with airway diameter. Airways exhibit a "strain limit" above which an abrupt dramatic rise in wall tension is observed.

Acid and particulate-induced aspiration lung injury in mice: importance of MCP-1

A model of aspiration lung injury was developed in WT C57BL/6 mice to exploit genetically modified animals on this background, i.e., MCP-1(-/-) mice. Mice were given intratracheal hydrochloric acid (ACID, pH 1.25), small nonacidified gastric particles (SNAP), or combined acid plus small gastric particles (CASP). As reported previously in rats, lung injury in WT mice was most severe for "two-hit" aspiration from CASP (40 mg/ml particulates) based on the levels of albumin, leukocytes, TNF-alpha, IL-1beta, IL-6, MCP-1, KC, and MIP-2 in bronchoalveolar lavage (BAL) at 5, 24, and 48 h. MCP-1(-/-) mice given 40 mg/ml CASP had significantly decreased survival compared with WT mice (32% vs. 80% survival at 24 h and 0% vs. 72% survival at 48 h). MCP-1(-/-) mice also had decreased survival compared with WT mice for CASP aspirates containing reduced particulate doses of 10-20 mg/ml. MCP-1(-/-) mice given 5 mg/ml CASP had survival similar to WT mice given 40 mg/ml CASP. MCP-1(-/-) mice also had differing responses from WT mice for several inflammatory mediators in BAL (KC or IL-6 depending on the particle dose of CASP and time of injury). Histopathology of WT mice with CASP (40 mg particles/ml) showed microscopic areas of compartmentalization with prominent granuloma formation by 24 h, whereas lung tissue from MCP-1(-/-) mice had severe diffuse pneumonia without granulomas. These results indicate that MCP-1 is important for survival in murine aspiration pneumonitis and appears to act partly to protect uninjured lung regions by promoting isolation and compartmentalization of tissue with active inflammation.

Quantification of lung water by transpulmonary thermodilution in normal and edematous lung

Purpose: To analyze the accuracy of the transpulmonary thermodilution method in the determination of extravascular lung water (EVLW). Material and Methods: Acute lung injury was produced in eight adolescent pigs weighing 28 to 35 kg by bronchoalveolar lung lavage. EVLW was measured by transpulmonary thermodilution method before and after the intratracheal introduction of 250 or 500 mL of saline solution in different lung injury conditions. No corrections for anatomic dead space were made. Results: When 250 mL was introduced, 195 ± 17 mL was detected in normal (uninjured) lungs versus 74 ± 57 mL in edematous (injured) lungs ( P < .05). When 500 mL was introduced, 343 ± 67 mL was detected in normal lungs versus 160 ± 51 mL in edematous lungs ( P < .001). Considering all determinations together, there was a very high negative correlation between the baseline EVLW and the percentage of EVLW detected (r = -0.92, P < .001). Conclusion: The transpulmonary thermodilution method is very accurate to detect changes in EVLW in normal lungs. In edematous lung, this method may underestimate the EVLW.

Atelectasis causes vascular leak and lethal right ventricular failure in uninjured rat lungs.

During mechanical ventilation, lung recruitment attenuates injury caused by high VT, improves oxygenation, and may optimize pulmonary vascular resistance (PVR). We hypothesized that ventilation without recruitment would induce injury in otherwise healthy lungs. Anesthetized rats were ventilated with conventional mechanical ventilation (VT 8 ml/kg; respiratory frequency 40 per minute) and 21% inspired oxygen, with or without a recruitment strategy consisting of recruitment maneuvers plus positive end-expiratory pressure, in the presence or absence of a laparotomy. Additional experiments examined the impact of atelectasis on right ventricular function using echocardiography, as well as functional residual capacity and PVR. Lack of recruitment resulted in reduced overall survival (59% nonrecruited vs. 100% recruited, p < 0.05), increased microvascular leak, greater impairment of oxygenation and lung compliance, increased PVR, and elevated plasma lactate. Echocardiography demonstrated that right ventricular dysfunction occurred in the absence of recruitment. Finally, samples from nonrecruited lungs demonstrated ultrastructural evidence of microvascular endothelial disruption. Although such effects clearly do not occur with comparable magnitude in the clinical context, the current data suggest novel mechanisms (microvascular leak, right ventricular dysfunction) whereby derecruitment may contribute to development of lung injury and adverse systemic outcome.

Unilateral lung injury.

Mechanical ventilation is a supportive lifesaving therapy that can potentially cause lung injury if periodic alveolar overdistension, or cyclic collapse, and reopening occur. The use of a low tidal volume with moderate to high positive end-expiratory pressure improves the survival of patients with acute lung injury and acute respiratory distress syndrome. Positioning the patient with the "good lung down" and using differential ventilation with selective positive end-expiratory pressure are the two currently accepted ventilatory strategies to be applied in patients with severe unilateral lung injury. However, both have serious limitations in clinical practice. Lung injury may be rather inhomogeneous-confined to one lung or preferentially distributed toward the dependent lung areas. In unilateral lung injury, ventilatory strategies that allow recruitment of injured lung and that avoid overdistension of uninjured lung parenchyma should be applied. Experimental studies have shown that the use of selective tracheal gas insufflation and partial liquid ventilation facilitates low tidal volume with appropriate gas exchange while reducing cyclic lung stretch and shear stresses. Further studies are needed to determine future applications of these therapies in humans.

Effects of Partial Liquid Ventilation on Unilateral Lung Injury in Dogs

The overall physiologic effect of partial liquid ventilation (PLV) in the setting of unilateral lung injury remains unclear. Therefore, we evaluated the effect of PLV on gas exchange in unilateral lung injury. Left unilateral lung injury was induced in 14 adult dogs by oleic acid instillation into a left pulmonary artery. The animals were divided into two groups: gas ventilation (GV) and PLV. During both GV and PLV, systemic blood gas levels were analyzed. Oxygen consumption (O(2)), carbon dioxide production (CO(2)) and pulmonary blood flow (Q) of both the right lung (uninjured lung) and left lung (injured lung) were measured. During PLV, O(2) of the injured left lung (o(2)-injured), CO(2) of the injured left lung (CO(2)-injured), and Q of the injured left lung (Q-injured) were greater than those in GV (O(2)-injured, 41.6 mL/min vs 23.4 mL/min, p = 0.006; CO(2)-injured, 34.4 mL/min vs 25.5 mL/min, p = 0.026; and Q-injured, 0.47 L/min vs 0.22 L/min, p = 0.002, respectively). However, overall PaO(2) during PLV was less than that during GV, likely due to either a redistribution of Q toward the injured lung (PLV Q-injured, 0.47 L/min vs GV Q-injured, 0.22 L/min; p = 0.002) or reduced gas exchange efficiency in the healthy lung. We conclude that in our model, PLV increases O(2) and VCO(2) in the injured lung. However, over all gas exchange efficiency is reduced.

EFFECTS OF A NOVEL ANTIOXIDANT DURING RESUSCITATION FROM SEVERE BLUNT CHEST TRAUMA

Previous work suggests that neutrophils (PMNs) and/or prostaglandins might mediate the progressive respiratory failure after severe pulmonary contusion. Since reactive oxygen metabolites are closely associated with both these factors, we examined the actions of a novel antioxidant after swine received a unilateral injury followed by 25% hemorrhage. An infusion (2mL/kg/h intravenously x 6 h) of either polynitroxylated 5% Dextran + Tempol (PND, n = 9), 5% Dextran (D, n = 6), or lactated Ringers (LR, n = 13) was begun 60 min post-injury to mimic 'pre-hospital resuscitation.' After 15 min, standard resuscitation was initiated (3x shed blood as LR in 30 min) plus further LR for 6 h to maintain hemodynamics. The total LR requirement was lower with PND (1,772+/-267 mL) versus D (3,040+/-689, P = 0.0563) or LR (4145+/-398, P = 0.0005). The ipsilateral bronchoalveolar lavage (BAL) PMN count with PND (8+/-2 x 10(5)/mL), was not different from its baseline (P = 0.131), but the counts with D (16+/-3) and LR (17+/-4) were both higher than their baselines (P = 0.0184 and 0.0431). Similarly, BAL protein with PND (1,560+/-350 mg %) was not elevated from its baseline (P = 0.0721), but the values with D (2,560+/-498) and LR (2,474+/-899) were both higher than their baselines (P = 0.0169 and 0.0325). In the contralateral (uninjured) lung, the effects were similar, but the increases were less for PMNs (8+/-2 versus 10+/-2 or 14+/-4 x 10(5)/mL) and for protein (609 +/-153 versus 1,955+/-671 or 1486+/-357 mg %). Despite these significant BAL changes, there was no obvious improvement in cardiopulmonary dysfunction. Thus oxidants probably have some role in the pathogenic mechanism of progressive secondary injury after thoracic trauma, but further work is needed to determine the therapeutic potential of antioxidants because no clinical improvement was detected.