Assessment of lung deposition and analysis of the effect of fluticasone/salmeterol hydrofluoroalkane (HFA) pressurized metered dose inhaler (pMDI) in stable persistent asthma patients using functional respiratory imaging.

BACKGROUND: Unambiguously for inhaled products, PK measures are best suited for ensuring that the total systemic exposure is equivalent for two products but cannot provide regional information about lung deposition and structural changes. Functional respiratory imaging (FRI) has been demonstrated to be sensitive for distinguishing small but imperative differences related to a single treatment. METHODS: In this study FRI is used in 16 asthmatic patients to assess equivalence in regional deposition for two products (fluticasone/salmeterol, test and reference) by directly measuring regional functional and structural changes within the lungs following its administration. RESULTS: No differences were observed between the lung deposition patterns and the effects on lung structure and function of two products, having the same formulation and manufactured by different organizations using FRI. CONCLUSIONS: Results using FRI complement PK assessments. The added value of this approach to the conventional clinical methods could be significant.

Asthma control with extrafine-particle hydrofluoroalkane-beclometasone vs. large-particle chlorofluorocarbon-beclometasone: a real-world observational study.

BACKGROUND: The extrafine-particle formulation of hydrofluoroalkane-beclometasone (EF HFA-BDP; Qvar®) demonstrates improved total and small airway deposition compared with large-particle chlorofluorocarbon (CFC)-BDP. In some short-term studies, EF HFA-BDP provides greater effects on lung function than CFC-BDP, and hence is recommended to be prescribed at a lower dose, but whether there are differences in asthma outcomes during long-term treatment is unknown. OBJECTIVE: To compare the effectiveness of EF HFA-BDP vs. CFC-BDP over 1 year. METHODS: This retrospective matched cohort study examined outcomes in a large primary care database for patients aged 5-60 years with asthma receiving their first inhaled corticosteroid (ICS) prescription (initiation population) or first ICS dose increase (step-up population) by a pressurized metered-dose inhaler (pMDI) as EF HFA-BDP or CFC-BDP. Patients were matched on baseline demographic and asthma severity measures in EF HFA-BDP:CFC-BDP ratios of 1:3 and 1:2 for initiation and step-up populations, respectively. Step-up patients were matched also on ICS dose during a baseline year. Co-primary endpoints were asthma control (composite measure comprising no recorded hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory infection) and exacerbation rate during the outcome year. RESULTS: For the initiation population (EF HFA-BDP n=2882; CFC-BDP n=8646), adjusted odds of achieving asthma control with EF HFA-BDP vs. CFC-BDP was 1.15 (95% CI 1.02-1.28). For the step-up population (n=258 and 516), adjusted odds of asthma control with EF HFA-BDP was 1.72 (95% CI 1.14-2.56). EF HFA-BDP was prescribed at a median dose half that of CFC-BDP. CONCLUSION AND CLINICAL RELEVANCE: During 1 year after initiating or stepping up ICS therapy by pMDI, patients who received EF HFA-BDP were more likely to achieve asthma control than those receiving CFC-BDP. These findings suggest that ICS formulation, particle size, and deposition characteristics play important roles in real-life effectiveness of asthma therapy. This study shows that an EF-particle formulation of beclometasone can be used at half the dose of the large-particle formulation with at least as good clinical outcomes.

Dual components of optimal asthma therapy: scientific and clinical rationale for the use of long-acting beta-agonists with inhaled corticosteroids.

The authors describe the scientific rationale for using an inhaled corticosteroid with an inhaled long-acting beta 2-agonist. They discuss the clinical trials demonstrating that using an inhaled corticosteroid with an inhaled long-acting beta 2-agonist provides greater overall asthma control compared with increasing the dose of inhaled corticosteroid. In addition, they review the clinical trials comparing the addition of a leukotriene modifier to an inhaled corticosteroid versus using an inhaled corticosteroid with an inhaled long-acting beta 2-agonist. Discussion also includes descriptions of trials showing reduced exacerbations of asthma when using an inhaled corticosteroid with an inhaled long-acting beta 2-agonist. Finally, the authors provide evidence for the ability to detect deteriorating asthma when using an inhaled corticosteroid with an inhaled long-acting beta 2-agonist, and they provide a comparison of salmeterol and formoterol, two long-acting beta 2-agonists.

Comparison of fluticasone propionate-salmeterol combination therapy and montelukast in patients who are symptomatic on short-acting beta(2)-agonists alone.

The objective of this study was to determine whether initial maintenance therapy for the treatment of inflammation and bronchoconstriction associated with persistent asthma is more effective with a combination product (100 microg of fluticasone propionate and 50 microg of salmeterol [FSC]) administered twice daily through the Diskus device (GlaxoWellcome, Research Triangle Park, NC) or with montelukast at 10 mg once daily. A 12-wk, randomized, double-blind, double-dummy, multicenter study was conducted with 423 patients 15 yr of age and older with asthma and who were symptomatic while receiving short-acting beta(2)-agonists alone. At end point, FSC resulted in significantly greater increases in morning predose FEV(1) (0.54 +/- 0.03 vs. 0.27 +/- 0.03 L), morning peak expiratory flow (PEF) (89.9 +/- 6.7 vs. 34.2 +/- 4.7 L/min), evening PEF (69.9 +/- 5.8 vs. 31.1 +/- 4.5 L/min), the percentage of symptom-free days (48.9 +/- 2.9 vs. 21.7 +/- 2.5%), the percentage of rescue-free days (53.0 +/- 2.8 vs. 26.2 +/- 2.5%), and the percentage of nights with no awakenings (23.0 +/- 2.5 vs. 15.5+/-2.4%) compared with montelukast (p < or = 0.001, all comparisons). FSC significantly reduced asthma symptom scores (-1.0 +/- 0.1 vs. -0.6 +/- 0.1), rescue albuterol use (-3.3 +/- 0.2 vs. -1.9 +/- 0.2 puffs/d), and the number of exacerbations (0 vs. 11) compared with montelukast (p < 0.001). Both treatments were well tolerated. In summary, treatment of the two main components of asthma (inflammation and bronchoconstriction) with fluticasone propionate and salmeterol in a combination product was a more effective initial maintenance treatment strategy than treatment with montelukast, a single-mediator antagonist.

Use of changes in symptoms to predict changes in lung function in assessing the response to asthma therapy.

BACKGROUND: The majority of adult patients with asthma are managed by primary care providers. Although there is no generally accepted gold standard for the assessment of asthma severity in general practice, treatment decisions and modifications to therapy are strongly influenced by patients' symptoms and history of asthma medication use. OBJECTIVES: The primary goal of this study was to determine whether there is a correlation between changes in asthma symptoms during treatment and changes in lung function, as measured by peak expiratory flow (PEF). A secondary goal was to compare the relative efficacy (in terms of improvement in asthma symptoms and lung function) of 3 commonly used asthma treatments: inhaled fluticasone propionate, inhaled salmeterol xinafoate, and oral zafirlukast. METHODS: This was a retrospective comparison employing regression analyses of asthma symptom and lung function data from 2890 male and female adolescent and adult patients with persistent asthma who were enrolled in 8 randomized, double-blind, double-dummy, parallel-group studies. Data on patients' self-rated symptoms, PEF, supplemental albuterol use, nighttime awakenings, and frequency of asthma exacerbations were used to ascertain whether there was a correlation between changes in asthma symptoms and changes in pulmonary function, and to compare treatment effects. RESULTS: Changes in patients' ratings of asthma symptoms after treatment with study medications showed a strong correlation with changes in lung function. Similarly, changes in lung function were strongly correlated with changes in supplemental beta-agonist use and quality of life. In addition, fluticasone or salmeterol treatment resulted in significantly greater increases in mean morning PEF (P < 0.001), significantly greater decreases in symptom scores (P < or = 0.004), significantly fewer nights with awakenings due to symptoms (P < or = 0.017), and significantly greater reductions in supplemental beta-agonist use (P < 0.001) compared with zafirlukast treatment or placebo. Patients treated with fluticasone or salmeterol also experienced significantly lower rates of asthma exacerbation (3%) during treatment than did those receiving zafirlukast (7%) or placebo (12%) (P < 0.001 and P = 0.015, fluticasone and salmeterol, respectively). CONCLUSION: These findings support the validity of primary care practitioners' basing asthma-management decisions on patients' symptoms.

Ileal VO(2)-O(2) alterations induced by endotoxin correlate with severity of mitochondrial injury.

Sepsis is usually associated with altered O(2) metabolism in systemic organs. Until recently, inadequate O(2) delivery was thought to be the putative mechanism underlying these metabolic alterations. However, current investigations suggest that impaired O(2) consumption due to disrupted O(2) use by mitochondria may be the culprit. Therefore, we hypothesized that endotoxin (LPS)-induced V O(2)- O(2) alterations would correlate with the severity of mitochondrial injury in a systemic organ (i.e., the ileum). Using an in situ autoperfused feline ileum preparation, we assessed V O(2)- O(2) relationships and mitochondrial ultrastructure after 2 h in LPS-treated (3 mg/kg, intravenous; n = 11) and time-matched control (n = 5) animals. Mitochondrial injury was graded in a blinded fashion on the basis of characteristics associated with established stages of cell injury. LPS-treated animals developed severe mitochondrial injury in the ileal mucosa despite unchanged regional tissue perfusion and ileal oxyhemoglobin levels compared with controls. Worsening of mitochondrial injury correlated with increases in the critical O(2) delivery (r = 0.85; p < 0.002) and decreases in the maximum O(2) extraction (r = -0.61; p < 0.02) in the ileum. These results suggest that mitochondrial injury, leading to impaired O(2) utilization, may be primarily responsible for altered V O(2)- O(2) relationships in systemic organs during sepsis.

The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD.

STUDY OBJECTIVES: To determine whether the combination of ipratropium bromide and albuterol results in greater and more consistent pulmonary function test (PFT) response rates than ipratropium bromide or albuterol alone in patients with COPD. DESIGN: Retrospective review of two recently completed 3-month, randomized, double-blind, parallel, multicenter, phase III trials. SETTING: Outpatient. PATIENTS: A total of 1,067 stable patients with COPD. INTERVENTIONS: Ipratropium bromide (36 microg qid), albuterol base (180 microg qid), or an equivalent combination of ipratropium bromide and albuterol sulfate (42 microg and 240 microg qid, respectively). MEASUREMENTS AND RESULTS: PFT response rates were analyzed using 12% and 15% increases in FEV1 compared with baseline values and were measured in the various treatment groups on days 1, 29, 57, and 85 in these trials. Regardless of whether a 12% or a 15% increase in FEV1 was used to define a positive response, an equivalent combination of ipratropium bromide and albuterol sulfate was superior to the individual agents (p < 0.05; all comparisons within 30 min). In addition, a 15% or more increase in FEV1 was seen in > 80% of patients who received the combination of ipratropium and albuterol sulfate during the initial PFT and continued to be observed 3 months after initial testing. CONCLUSIONS: Use of a combination of ipratropium bromide and albuterol sulfate is superior to the individual agents in identifying PFT reversibility in patients with COPD.

Endotoxin-induced ileal Vo2-Do2 alterations do not correlate with the severity of ileal injury.

PURPOSE: Altered Vo2-Do2 relationships are most often noted to occur in the setting of sepsis or endotoxin (LPS)-induced systemic organ microvascular injury and are generally thought to be causally linked to that injury. However, we have recently shown that ileal microvascular injury is not associated with altered ileal Vo2-Do2, relationships. Thus, we hypothesized that the severity of LPS-induced systemic organ microvascular injury would not correlate with the development of systemic organ Vo2-Do2 alterations. MATERIALS AND METHODS: To test this hypothesis, we used the in situ autoperfused feline ileal preparation to simultaneously examine microvascular permeability, reflected as the ileal lymph to plasma protein concentration ratio (CL/CP), and ileal Vo2-Do2 relationships 2 hours after intravenous LPS (0.75-2.0 mg/kg; n = 9) and in matching controls (n = 5). RESULTS: As expected, all LPS-treated animals were found to have extensive ileal histological damage and marked increases in the CL/CP compared with controls (0.308 +/- 0.019 v 0.097 +/- 0.009; P < .001). In addition, although the critical Do2 (Do2c) was elevated in the LPS-treated animals relative to controls (34.2 +/- 5.0 v 16.7 +/- 1.4 mL/min/kg; P < .03), there was no correlation between the Do2c and the CL/CP in the LPS-treated animals. Finally, ileal wet to dry weight ratios after LPS did not differ from controls. CONCLUSION: Taken together, these data suggest that factors other than organ injury, as assessed by morphological and permeability alterations, are important in the pathogenesis of altered systemic organ Vo2-Do2 relationships after LPS.

Ischemia/reperfusion injury to the ileum does not account for the ileal VO2-DO2 alterations induced by endotoxin.

PURPOSE: Endotoxin (lipopolysaccharide [LPS])-induced systemic organ injury leads to disruption of normal systemic organ metabolic processes, which are manifest clinically by signs of accelerated anaerobic metabolism (e.g., tissue acidosis and hyperlactatemia) and altered VO2-DO2 relationships. The association of increased anaerobic metabolism with VO2-DO2 alterations has led to the notion that ischemia/ reperfusion (I/R) injury may be a prerequisite for the development of VO2-DO2 alterations during endotoxemia. However, in contrast to sepsis, in which oxygen consumption is often increased, oxygen consumption is severely decreased after I/R injury. Based on these observations, we hypothesized that I/R injury would result in systemic organ VO2-DO2 alterations, which are distinct from those that occur in sepsis. MATERIALS AND METHODS: We used the in situ autoperfused feline ileal preparation to simultaneously examine microvascular permeability, reflected as the ileal lymph to plasma protein concentration ratio (CL/CP), and ileal VO2-DO2 relationships after either intravenous LPS (2.0 mg/kg; n = 5) or I/R injury (n = 5), and in matching controls (n = 5). RESULTS: As expected, all LPS-treated and I/R-injured animals were found to have extensive ileal histological damage and marked increases in the CL/CP compared with controls (0.315 +/- 0.009 and 0.329 +/- 0.034, respectively, v 0.097 +/- 0.009; P < .001, both comparisons). In addition, the critical DO2 (DO2c) was elevated, and the critical oxygen extraction was decreased in both the I/R and LPS groups relative to controls. However, as initially hypothesized, the VO2 at the critical DO2 was markedly decreased in the I/R group compared with that of the LPS group. CONCLUSIONS: These data indicate that I/R injury is insufficient to account for the systemic organ VO2-DO2 alterations that occur with LPS injury.

Metabolic consequences of sepsis. Correlation with altered intracellular calcium homeostasis.

The availability of adequate substrate for energy homeostasis is a minimal requirement for vital organ function that normally is provided through dietary intake. When dietary sources of nutrients are inadequate, the body relies on alternate sources of energy provided by gluconeogenesis, lipolysis, and ketogenesis. Sepsis is associated with disruption of virtually all these provisional sources of energy substrate (see Fig. 4). In addition, sepsis impairs the function of the glycolytic pathway, the integrity of which is necessary for glucose to be used effectively for energy production. These abnormalities, coupled with disruption of the intracellular energy-producing machinery (e.g., glycolytic and gluconeogenic enzymes, mitochondria) eventually lead to a reduction in intracellular ATP. Furthermore, a reduction in intracellular ATP can undermine virtually all the energy-consuming functions of the cell, including energy substrate formation (e.g., failed gluconeogenesis), antioxidant production, and calcium homeostasis. High levels of intracellular calcium, in turn, are known to activate many potentially destructive enzymatic pathways (e.g., proteases, phospholipases, endonucleases) that further diminish cell function and may result in cell death. In this context, iCa2+ accumulation may play an important role in the progression from early sepsis to MODS, the most common cause of mortality in the ICU.

Acid aspiration results in ileal injury without altering ileal V(O2)-D(O2) relationships.

Systemic organ endothelial injury and V(O2)-D(O2) relationship alterations occur frequently in the setting of acute lung injury, and they are believed to play an important role in the pathogenesis of the multiple organ dysfunction syndrome (MODS). However, the relationship, if any, between systemic organ endothelial injury and V(O2)-D(O2) relationship alterations remains unknown. We hypothesized that microvascular endothelial injury and attendant interstitial edema would result in increased diffusion distances for oxygen and altered systemic organ V(O2)-D(O2) relationships. To test this hypothesis, we utilized the in situ autoperfused feline ileal preparation to evaluate ileal V(O2)-D(O2) relationships in control animals (n = 5) and in animals with HCl-induced acute lung and systemic organ injury (n = 5). As expected, ileal endothelial protein permeability (CL/CP) was increased in HCl-injured animals compared to control animals (0.187 +/- 0.024 versus 0.097 +/- 0.009; p < 0.01). However, contrary to our original hypothesis and despite marked morphologic and endothelial protein permeability alterations, ileal V(O2)-D(O2) relationships were not altered in the HCl-injured animals. Moreover, V(O2)-D(O2) relationships in the ileum remained unchanged even when ileal venous pressures were increased to 15 mm Hg. Taken together, these findings do not support an important role for oxygen diffusion limitation in the pathogenesis of altered systemic organ V(O2)-D(O2) relationships.

Diagnosis and therapy of acute respiratory distress syndrome in adults: an international survey.

In an attempt to identify the range of opinions influencing the diagnosis and therapy of patients with the adult respiratory distress syndrome (ARDS), a postal survey was mailed to 3,164 physician members of the American Thoracic Society Critical Care Assembly. The questionnaire asked opinions regarding the factors important in the diagnosis of ARDS and its treatment. Thirty-one percent of physicians surveyed responded within 4 weeks, the vast majority of which were board certified or eligible in Internal Medicine, Pulmonary Disease, and/or Critical Care Medicine. A known predisposing cause, measure of oxygenation efficiency, and a chest radiograph depicting pulmonary edema were reported to be the most important criteria for a clinical and research diagnosis of ARDS. Lung compliance and bronchoalveolar lavage neutrophil or protein content were reportedly less important. The initial treatment of patients with ARDS was reported to be most commonly accomplished using volume-cycled ventilation in the assist/control mode. Nearly half the responders reported using lower tidal volumes (5 to 9 mL/kg) than the traditionally recommended 10 to 15 mL/kg. Most respondents indicated they have intentionally allowed CO2 retention. On average, oxygen toxicity was thought to begin at an FIO2 between 0.5 and 0.6. It was reported that modest levels of positive end-expiratory pressure (PEEP) were used in incremental fashion as FiO2 requirements increased. Perceived indications for insertion of pulmonary artery catheters and compensation of the effects of PEEP on the pulmonary artery occlusion pressure varied widely among the responders. We conclude that reported practice patterns regarding the care of ARDS patients vary widely even within a relatively homogenous group of critical care practitioners.

Anti-CD18 antibody does not block ileal injury induced by phorbol myristate acetate.

Acute lung injury (ALI) is frequently complicated by systemic microvascular injury. In previous studies, ALI from acid aspiration resulted in ileal microvascular injury. This was due to systemic inflammation and was prevented by MoAb 60.3, an antibody against the CD18 antigen that mediates leukocyte adherence. The present study was designed to test the hypothesis that ileal microvascular injury during phorbol myristate acetate (PMA)-induced systemic inflammation is also blocked by MoAB 60.3. We assessed the injury by measuring the concentration ratios of lymph protein to plasma protein (i.e., CL/CP) at steady-state lymph flows in autoperfused cat ileum preparations. As expected, the CL/CP increased in the ilea of animals given PMA (15 micrograms/kg; n = 5) compared with the ilea of control animals (n = 5) (0.202 +/- 0.024 versus 0.106 +/- 0.010; p = 0.006) and was accompanied by widespread morphologic alterations. Intravenously administering MoAb 60.3 (2 mg/kg) to animals before the PMA infusion (n = 5) yielded a CL/CP value indistinguishable from that of the PMA group (0.222 +/- 0.024 versus 0.202 +/- 0.024; p = NS). These results suggest that CD18-mediated leukocyte adherence is not important in the mechanism of PMA-induced ileal microvascular injury.

Gastrointestinal tract dysfunction in critical illness: pathophysiology and interaction with acute lung injury in adult respiratory distress syndrome/multiple organ dysfunction syndrome.

The adult respiratory distress syndrome (ARDS), a common complication of critical illness, is associated with a > 50% mortality rate. Refractory respiratory failure is, however, an uncommon cause of mortality in these patients. Most deaths are due to a syndrome of relentless organ dysfunction accompanied by abnormal organ system interactions, collectively referred to as the multiple organ dysfunction syndrome (MODS). MODS is associated with two chief pathophysiologic derangements: a) the unregulated activation of systemic inflammatory cascades; and b) alterations of oxygen uptake (VO2)-oxygen delivery (DO2) relationships. Current concepts regarding the pathophysiology of MODS, specifically its relationship to unregulated systemic inflammation and alterations in VO2-DO2 alterations, are discussed. Within this framework, current and future areas for investigation that may result in mechanism-specific innovations with the potential to interrupt events mediated by gastrointestinal dysfunction that lead to MODS are presented.

Regional blood flow distribution in endotoxin-treated dogs: modification by ibuprofen.

PURPOSE: The aim of this study was to determine whether the improved hemodynamic profiles reported with cyclooxygenase inhibition during sepsis include improvements in tissue perfusion is unknown. Our hypothesis was that cyclooxygenase inhibition with ibuprofen will prevent the endotoxin-induced alterations in regional blood flow distribution from developing and/or restore the endotoxin-induced loss of responsiveness to intravascular volume expansion. METHODS: We measured cardiac output, regional blood flow, and total systemic shunt flow in dogs using radiolabeled 15-microns microspheres. These parameters were assessed in control (N = 10) and endotoxin-treated animals (N = 7). Additional endotoxin-treated animals (N = 7) were also pretreated with ibuprofen. RESULTS: Compared with controls, endotoxin-treated animals exhibited marked reductions in blood flow to most systemic organs that were not reversed with large, intravenous saline infusions (ie, isotonic saline; 40 mL/kg; N = 4). By contrast, although ibuprofen pretreatment (12.5 mg/kg; N = 7) completely prevented the reductions in mean arterial pressure caused by endotoxin from occurring, it did little to prevent the development of endotoxin-induced alterations in regional blood flow distribution. Nonetheless, in contrast to the endotoxin-treated animals, there were significant increases in cardiac output and blood flow to several organs after saline infusion in the ibuprofen-pretreated animals. CONCLUSIONS: Cyclooxygenase inhibition with ibuprofen has few direct effects on regional blood flow distribution after endotoxin. However, cyclooxygenase inhibition with ibuprofen does attenuate the endotoxin-induced decrease in vascular responsiveness to intravenous saline infusion.

Paraaminosalicylate blocks that ileal injury induced by phorbol myristate acetate.

Activation of neutrophils with the release of oxidant radicals has been implicated in the pathogenesis of gut injury in inflammatory bowel disease (IBD). The pathogenesis of gut injury in the multiple organ dysfunction syndrome associated with acute lung injury, although less focal, appears to be similar. Paraaminosalicylate (PAS) has been shown to be effective in treating IBD, most likely because of its ability to scavenge oxidant radicals. The present study was therefore designed to test the hypothesis that PAS attenuates the gut injury typically seen during systemic neutrophil activation by phorbol myristate acetate (PMA). We assessed gut injury by measuring the concentration ratio of lymph to plasma protein (CL/CP) at steady-state lymph flows in autoperfused cat ileum preparations. As expected, the CL/CP increased in animals given PMA (15 micrograms/kb; n = 6) compared with control animals (n = 5) (0.205 +/- 0.033 versus 0.118 +/- 0.004; p = 0.04) 0.04) and were accompanied by morphologic alterations. In contrast, the intravenous administration of PAS (100 mg/kg) to animals prior to PMA infusion (n = 5) yielded a CL/CP value indistinguishable from that in control animals (0.113 +/- 0.017 versus 0.118 +/- 0.004). Additional in vitro studies suggested that the protective effects of PAS were not the result of altered neutrophil margination, chemotaxis, or oxidant burst. Although PAS appeared to protect the ileum from PMA-induced microvascular injury, it had no protective effects on the lungs.

Cryptogenic bronchiolitis.

Cryptogenic bronchiolitis is a unique clinical disorder that causes rapidly progressive, chronic airflow obstruction. In this article, we reviewed the pathology, clinical characteristics, and proposed pathogenesis of cryptogenic bronchiolitis. It is evident that cryptogenic bronchiolitis represents the result of a disordered inflammatory response in the small airways of the lung. The clinical characteristics of cryptogenic bronchiolitis, in most instances, should allow this disorder to be distinguished from other causes of chronic airflow obstruction, as well as from BOOP. In this regard, a high clinical suspicion and an awareness of its unique clinical features are the keys to the diagnosis of cryptogenic bronchiolitis.

Acid aspiration-induced acute lung injury causes leukocyte-dependent systemic organ injury.

The adult respiratory distress syndrome is a form of acute lung injury (ALI) that is frequently associated with systemic organ injury and often occurs in the setting of wide-spread inflammatory cell activation. However, whether conditions that lead to ALI result in systemic organ injury is unclear. This study was designed to test the hypothesis that ALI induced by acid aspiration will not result in systemic organ injury. Morphological alterations and lymph-to-plasma protein ratios were measured in autoperfused cat ileum preparations of four control animals and five animals with ALI produced by the endobronchial instillation of 0.1 N HCl (0.5 ml.kg-1.lung-1). After 2 h, the lymph-to-plasma protein ratio (a measure of microvascular permeability) was increased in the ilea of HCl-injured animals compared with control animals (0.234 +/- 0.03 vs. 0.121 +/- 0.005; P = 0.012) and was accompanied by extensive morphological alterations. Four additional HCl-injured animals were pretreated with an antileukocyte adherence antibody (anti-CD18, 2 mg/kg) that blocked the HCl-induced alterations in the ileum. This study provides evidence for significant systemic organ injury after acid aspiration-induced ALI and suggests that the neutrophil may be a key mediator.