Lung abscess: the non-conservative management: a narrative review.

Background and Objective: Systemic antibiotics are the best treatment options for lung abscesses. However, up to 37% of lung abscesses do not respond to antibiotics and may require additional interventions. Percutaneous transthoracic tube drainage (PTTD), endoscopic catheter drainage (ECD) and surgical resection are additional options available when first line therapy with systemic antibiotics are unsuccessful. In this narrative review, we summarize all available interventional procedures, techniques, complications, safety, and contraindications. Methods: A literature search was performed using Medline/PubMed from January 1980 to October 2023. Key words: "lung abscess", "pulmonary abscess", "endoscopic drainage", "percutaneous drainage", "tube drainage". Pediatric patients were excluded from this study. Key Content and Findings: PTTD and ECD are fairly safe procedures. Performing PTTD or ECD without delay may shorten the duration of hospital stay. This may lower the burden on health care. Moreover, draining abscesses may relieve discomfort in the clinical symptoms associated with abscesses. The primary factor in choosing ECD over PTTD is the location of the abscess, and the presence of a bronchial airway leading to the abscess for successful ECD. ECD has lower rate of complications and mortality; and similar success rate compared to PTTD. While mortality has been reported with PTTD, ECD appears to be safer according to present data. Conclusions: PTTD and ECD are safe procedures, with low complication rates. ECD has a lower complication rate than PTTD does.

Safety and Feasibility of Photodynamic Therapy for Ablation of Peripheral Lung Tumors.

BACKGROUND: Newer navigational bronchoscopy technologies render peripheral lung lesions accessible for biopsy and potential treatment. We investigated whether photodynamic therapy (PDT) delivered via navigational bronchoscopy is feasible and safe for ablation of peripheral lung tumors. METHODS: Two studies evaluated PDT in patients with solid peripheral lung tumors followed by clinical follow-up (nonresection study, N=5) or lobectomy (resection study, N=10). Porfimer sodium injection was administered 40 to 50 hours before navigational bronchoscopy. Lesion location was confirmed by radial probe endobronchial ultrasonography. An optical fiber diffuser was placed within or adjacent to the tumor under fluoroscopic guidance; laser light (630 nm wavelength) was applied at 200 J/cm of diffuser length for 500 seconds. Tumor response was assessed by modified Response Evaluation Criteria in Solid Tumors at 3 and 6 months postprocedure (nonresection study) and pathologically (resection study). RESULTS: There were no deaths, discontinuations for adverse events, or serious or grade ≥3 adverse events related to study treatments. Photosensitivity reactions occurred in 8 of 15 patients: 6 mild, 1 moderate, 1 severe (elevated porphyrins noted in blood after treatment). Among 5 patients with clinical follow-up, 1 had complete response, 3 had stable disease, and 1 had progressive disease at 6 months follow-up. Among 10 patients who underwent lobectomy, 1 had no evidence of tumor at resection (complete response), 3 had 40% to 50% tumor cell necrosis, 2 had 20% to 35%, and 4 had 5% to 10%. CONCLUSION: PDT for nonthermal ablation of peripheral lung tumors was feasible and safe in this small study. Further study is warranted to evaluate efficacy and corroborate the safety profile.

Effect of Routine Clopidogrel Use on Bleeding Complications After Endobronchial Ultrasound-guided Fine Needle Aspiration.

BACKGROUND: Endobronchial ultrasonography has proven to be highly sensitive and specific in the diagnoses of patients with mediastinal and hilar adenopathy. Many of these patients are on a combination of clopidogrel (a compound that inhibits adenosine diphosphate-induced platelet aggregation) and aspirin due to neurological and/or cardiac-related comorbidities, and stopping anticoagulation may place these patients at high risk for potential complications. Our group has previously showed that thoracentesis with an 8-french catheter is safe in patients receiving clopidogrel and aspirin with low risk of complications. In this manuscript, we report the outcomes of the largest prospective multicenter series of patients undergoing endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) while receiving clopidogrel. METHODS: Patients presenting to our institutions with mediastinal/hilar adenopathy, requiring EBUS-TBNA, and actively taking clopidogrel and aspirin were included in the study. If the medication could be held for 5 to 7 days before the procedure, the patient was excluded. EBUS-TBNA was performed by an interventional pulmonology faculty on a total of 42 patients. All patients received total intravenous anesthesia, and a total of 92 nodes were sampled. First, 3 passes were performed with a 22-G needle. If no complications were encountered, we followed with additional 3 passes with a 21 G. Rapid onsite evaluation was performed in all patients. Bleeding at the puncture site was considered significant if it required cold saline, topical sympathomimetic, or balloon tamponade for hemostasis. Bleeding was considered nonsignificant if no interventions were required to achieve hemostasis. RESULTS: We were able to perform all procedures successfully using both the 21 and 22-G needles. One patient required 30 mL cold saline installation to accomplish hemostasis with the 21 and 22-G needles. Our yield was comparable with the current literature. No statistically significant complications occurred during the procedure. All patients were contacted within 24 hours, and none reported bloody sputum. CONCLUSION: We suggest that EBUS-TBNA, using 22 and 21-G needles, is safe with high yields in patients with mediastinal/hilar adenopathy, actively taking clopidogrel and aspirin, and are at high risk for thrombotic complications if the medication is discontinued.

Electromagnetic Navigation Bronchoscopy for Peripheral Pulmonary Lesions: One-Year Results of the Prospective, Multicenter NAVIGATE Study.

INTRODUCTION: Electromagnetic navigation bronchoscopy (ENB) is a minimally invasive technology that guides endoscopic tools to pulmonary lesions. ENB has been evaluated primarily in small, single-center studies; thus, the diagnostic yield in a generalizable setting is unknown. METHODS: NAVIGATE is a prospective, multicenter, cohort study that evaluated ENB using the superDimension navigation system (Medtronic, Minneapolis, Minnesota). In this United States cohort analysis, 1215 consecutive subjects were enrolled at 29 academic and community sites from April 2015 to August 2016. RESULTS: The median lesion size was 20.0 mm. Fluoroscopy was used in 91% of cases (lesions visible in 60%) and radial endobronchial ultrasound in 57%. The median ENB planning time was 5 minutes; the ENB-specific procedure time was 25 minutes. Among 1157 subjects undergoing ENB-guided biopsy, 94% (1092 of 1157) had navigation completed and tissue obtained. Follow-up was completed in 99% of subjects at 1 month and 80% at 12 months. The 12-month diagnostic yield was 73%. Pathology results of the ENB-aided tissue samples showed malignancy in 44% (484 of 1092). Sensitivity, specificity, positive predictive value, and negative predictive value for malignancy were 69%, 100%, 100%, and 56%, respectively. ENB-related Common Terminology Criteria for Adverse Events grade 2 or higher pneumothoraces (requiring admission or chest tube placement) occurred in 2.9%. The ENB-related Common Terminology Criteria for Adverse Events grade 2 or higher bronchopulmonary hemorrhage and grade 4 or higher respiratory failure rates were 1.5% and 0.7%, respectively. CONCLUSIONS: NAVIGATE shows that an ENB-aided diagnosis can be obtained in approximately three-quarters of evaluable patients across a generalizable cohort based on prospective 12-month follow-up in a pragmatic setting with a low procedural complication rate.

Emerging Perspectives on mTOR Inhibitor-Associated Pneumonitis in Breast Cancer.

Substantial improvements in the early detection and treatment of breast cancer have led to improvements in survival, but breast cancer remains a significant cause of morbidity and mortality in women. In 2012, the mammalian target of rapamycin (mTOR) inhibitor everolimus was approved by the U.S. Food and Drug Administration for the treatment of advanced breast cancer in patients resistant to endocrine therapy. Although everolimus is generally well tolerated, mTOR inhibitor-associated pneumonitis is one of the most common adverse drug events leading to treatment discontinuation. To date, the underlying pathophysiology of this toxicity is unclear, and this uncertainty may hinder the optimization of management strategies. However, experiences from breast cancer and renal cell carcinoma clinical trials indicate that mTOR inhibitor-associated pneumonitis can be effectively managed by early detection, accurate diagnosis, and prompt intervention that generally involves everolimus dose reductions, interruptions, or discontinuation. Management can be achieved by a multidisciplinary approach that involves the collaborative efforts of nurses, oncologists, radiologists, infectious disease specialists, pulmonologists, clinical pharmacists, and pathologists. Comprehensive education must be provided to all health care professionals involved in managing patients receiving everolimus therapy. Although general recommendations on the management of mTOR inhibitor-associated pneumonitis have been published, there is a lack of consensus on the optimal management of this potentially serious complication. This article provides an overview of mTOR inhibitor-associated pneumonitis, with a focus on the detection, accurate diagnosis, and optimal management of this class-related complication of mTOR inhibitor therapy. IMPLICATIONS FOR PRACTICE: This article summarizes the pathogenesis, clinical presentation, incidence, detection, and optimal management of everolimus-related noninfectious pneumonitis in breast cancer. In particular, this article provides a detailed overview of the important aspects of the detection, accurate diagnosis, and appropriate management of mammalian target of rapamycin inhibitor-associated pneumonitis. In addition, this article emphasizes that effective management of this adverse drug event in patients with breast cancer will require a multidisciplinary approach and collaboration among various health care professionals.

Mediastinal and Hilar Lymph Node Measurements. Comparison of Multidetector-Row Computed Tomography and Endobronchial Ultrasound.

RATIONALE: Multidetector-row chest computed tomography scan is a common initial imaging modality and endobronchial ultrasound is a minimally invasive diagnostic tool used to evaluate enlarged lymph nodes, but comparisons of imaging results are lacking. OBJECTIVES: To determine the size of thoracic lymph nodes and the strength of agreement between each measurement from coronal plane computed tomography and static endobronchial ultrasound images. METHODS: A retrospective review of consecutive patients who underwent endobronchial ultrasound-transbronchial needle aspiration of their lymph nodes because of clinical suspicion of benign or malignant thoracic disease. MEASUREMENTS AND MAIN RESULTS: One hundred and twenty-four lymph nodes from the mediastinal (74.2%) and hilar (25.8%) stations were measured in 59 patients (mean age, 64.5 yr; 33 males). The mean (standard deviation) short-axis diameter on computed tomography was 14.1 (6.7) mm compared with 12.6 (6.6) mm on endobronchial ultrasound. Benign lymph nodes (n = 42) were larger on computed tomography than on endobronchial ultrasound (14.1 [6.2] vs. 11.5 [6.2] mm). Malignant lymph nodes (n = 35) were larger on endobronchial ultrasound than on computed tomography (17.3 [6.4] vs. 16.2 [6.7] mm). Sixty-five percent of the lymph nodes that were initially interpreted as not enlarged on axial computed tomography images measured greater than 10 mm on each imaging modality (12.5 [5.9] mm on computed tomography and 10.5 [5.6] mm on endobronchial ultrasound) and 24% of the sampled lymph nodes from this group contained malignant cells. Random-effects maximal likelihood linear regression showed a statistically significant difference between endobronchial ultrasound and the computed tomography method for measuring short-axis diameter in all 124 lymph nodes. There was a weak agreement (intraclass correlation, rho: 0.44 [95% confidence interval, 0.31-0.59]) between short-axis diameter measurements from each imaging modality. CONCLUSIONS: Our single-center study shows that there was poor correlation between computed tomography and endobronchial ultrasound for the measurement of mediastinal and hilar lymph nodes. Malignant cells were recovered by ultrasound-guided needle aspiration from a substantial fraction of lymph nodes that were initially interpreted as normal in size. If these findings are confirmed, new criteria may be needed for lymph node measurement on computed tomography that will guide selection of lymph nodes for endobronchial ultrasound-transbronchial needle aspiration.

Bronchoscopic lung volume reduction.

The management of obstructive lung disease, particularly emphysematous lung disease, is aggressively being pursued. The patient populations that will experience the greatest benefit with lung volume reduction are those that are the worst candidates for surgical intervention. Identifying a bronchoscopic approach that has a true impact on this patient population will be a major accomplishment in the management of patients with chronic obstructive pulmonary disease. This article highlights the work currently ongoing in the area of bronchoscopic lung volume reduction. There are tools now clinically available in some locations throughout the world, but no standardized technique exists.

Dyspnea in a patient with Mounier-Kuhn syndrome.

Poorly differentiated non-small cell lung carcinoma with a component of sarcoma-like (spindle and/or giant cells) or sarcoma (malignant bone, cartilage, or skeletal muscle) cells are called pleomorphic carcinoma. These carcinoma represent one of the 5 subtypes of rare pulmonary malignancies collectively classified as sarcomatoid carcinoma by the World Health Organization histologic classification of lung tumors. The pathogenesis of sarcomatoid carcinoma remains unclear, and treatment of this malignant tumor is less defined. Very few cases of sarcomatoid carcinoma involving the upper respiratory tract have been reported in the literature. We report here an atypical presentation and location of this tumor (in the trachea), causing obstruction with a positional ball-valve effect, in a patient with tracheobronchomegaly (Mounier-Kuhn syndrome). In addition, we discuss the recurrent nature of the disease and the potential therapeutic difficulties.

Comparative cost analysis of endobronchial ultrasound-guided and blind TBNA in the evaluation of hilar and mediastinal lymphadenopathy.

BACKGROUND: The superior accuracy of endobronchial ultrasound (EBUS) averts many diagnostic surgical procedures. This likely leads to significant cost savings despite an increased per procedure cost. We sought to compare the true costs of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) compared with "blind" fiberoptic bronchoscopy-transbronchial needle aspiration (FB-TBNA) factoring in the impact of diagnostic surgical procedures in the diagnosis of mediastinal lymphadenopathy. METHODS: In this retrospective case study, we selected 294 patients with thoracic lymphadenopathy as diagnosed by computed tomography at a university hospital. Information was extracted from the electronic record. Costs were determined from the Centers for Medicare and Medicaid Services resource-based relative value scale. We defined a positive diagnosis as one where benign or malignant disease was found. A negative biopsy was one where lymph node sampling was confirmed, but no pathology (benign or malignant) was seen. A nondiagnostic biopsy was one where no pathology was seen and lymph node sampling could not be confirmed. The total cost of endoscopic and surgical diagnostic procedures was tallied for each patient to obtain mean costs per patient. RESULTS: Thirty-seven patients underwent FB-TBNA and 257 underwent EBUS-TBNA. A diagnosis was found in 90% of patients in the EBUS group and 62.2% of patients in the FB-TBNA group (P<0.001). More patients in the FB-TBNA group underwent a diagnostic surgical procedure (HR= -0.1573, 95% confidence interval, -0.30 to -0.15; P<0.001). After accounting for all diagnostic procedures, the mean savings with EBUS was $1071.09 (P=0.09) per patient. CONCLUSIONS: EBUS-TBNA is less expensive than blind FB-TBNA in the evaluation of thoracic lymphadenopathy when accounting for diagnostic surgical procedures.

Effect of routine clopidogrel use on bleeding complications after ultrasound-guided thoracentesis.

BACKGROUND: Thoracentesis is one of the most commonly performed medical procedures with an excellent safety profile. Clopidogrel (a compound that inhibits adenosine diphosphate-induced platelet aggregation) is often prescribed for primary or secondary prevention of cardiovascular disease and has been associated with bleeding complications in patients undergoing surgical procedures. The purpose of this study was to assess the safety of ultrasound (US)-guided thoracentesis in patients receiving clopidogrel therapy. METHODS: Data were collected on 30 consecutive patients taking clopidogrel without other known underlying coagulation problems. These patients underwent 45 US-guided thoracenteses over 26 months. Clopidogrel was not discontinued before the thoracentesis in patients presenting with symptomatic pleural effusion. Thoracenteses were performed in these patients and the incidence of bleeding and other complications among patients was reported. RESULTS: Between June 2009 and August 2011, there were 30 consecutive patients on clopidogrel at the time of thoracenteses. These patients presented with respiratory distress because of pleural effusion and underwent a total of 45 thoracenteses. There was no significant bleeding or other complications in this patient population. No patient required transfusion after the procedure. CONCLUSION: Patients who are receiving clopidogrel and present with symptomatic pleural effusion can safely undergo US-guided thoracentesis without interrupting clopidogrel before the procedure. Larger studies are required to confirm these results.

Pyogenic granuloma of the distal trachea: a case report.

Pyogenic granuloma (PG), also known as lobular capillary hemangioma, is a common, acquired, non-neoplastic, vascular lesion that is often found on the skin and oral mucosa. The term "pyogenic granuloma" is a misnomer, as the lesion does not contain purulent material and is not a granuloma. Lesions have also been reported in the gastrointestinal tract and during pregnancy. PG is a smooth or lobulated, red lesion on a sessile or pedunculated base that varies in size from a few millimeters and rarely exceeds 2.5 cm. The etiology of PG remains unclear but they are thought to develop spontaneously or after local minor trauma where excess production of angiogenic growth factors have been implicated. Trachea PG lesion is rare and there is only 1 known report in the literature. Our case is unique, given the location of the lesion and our treatment using bronchoscopic cryosurgery.

Central intranodal vessels to predict cytology during endobronchial ultrasound transbronchial needle aspiration.

BACKGROUND: : There has been recent interest in identifying the endoscopic ultrasonographic characteristics of lymph nodes (LNs) that predict the presence or absence of malignant involvement. Normal LN anatomy includes the presence of a central intranodal blood vessel (CIV) that can be obliterated with invasion of malignant cells. We sought to determine whether examining LNs for the presence or absence of a CIV during endobronchial ultrasound (EBUS) could predict benign or malignant cytology of the samples obtained. METHODS: : We prospectively evaluated patients undergoing EBUS-transbronchial needle aspiration (TBNA) for mediastinal or hilar adenopathy in a tertiary care referral center. All LNs were prospectively characterized as having or not having a CIV and subsequently classified as benign or malignant by cytologic analysis. RESULTS: : A total of 56 patients undergoing EBUS-TBNA were evaluated. One hundred three LNs were available for analysis. Fifty-six of 103 LNs were positive for malignancy (54.3%). Ultrasonographic identification of a CIV was associated with benign LN cytology with a sensitivity of 83.0% and a specificity of 91.1% and an OR of 49.7 (95% confidence interval, 15.1-163.9). Finding a CIV had a positive predictive value for benign LN cytology of 88.6%. The absence of finding a CIV had a positive predictive value for malignant cytology of 86.4%. The presence or absence of a CIV had an overall diagnostic accuracy of 87.4% (correctly categorizing 90 of 103 LNs). CONCLUSIONS: : There are morphologic characteristics of LNs that can be visualized at the time of EBUS to help predict whether the nodes being evaluated have malignant involvement. The presence of a CIV suggests that the node is benign, whereas the absence of a central intranodal vessel increases the likelihood of malignancy. The presence or absence of a CIV has a good overall accuracy in predicting malignancy (87.4%).

A rare nonmalignant mass of the pancreas: case report and review of pancreatic sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown etiology affecting patients from all genetic backgrounds. Pancreatic involvement is rare; the first case was described on autopsy in 1937. We present a case of pancreatic sarcoidosis without a history of the disease presenting as biliary obstruction mimicking pancreatic malignancy. We also review the literature with respect to management and outcomes of similar cases. The patient described here presented with all the signs and symptoms of a pancreatic malignancy, which was confirmed on a CT scan; the positron emission tomography scan and the CA 19-9 level were also confirmatory of the suspected diagnosis. In this setting, if the mass looks resectable, a Whipple procedure would be the next logical step. However, such strategy would be aggressive management for a benign condition that could be palliated with diverting rather than resective procedures without changing the outlook of the disease. We suggest keeping a high index of suspicion in patients with a history of the disease if demographic concordance exists.

Mechanical ventilation exacerbates alveolar macrophage dysfunction in the lungs of ethanol-fed rats.

BACKGROUND: Patients with alcohol abuse have a two- to three-fold increased risk of acute lung injury and respiratory failure after sepsis or trauma but are also at increased risk of nosocomial pneumonia. Mechanical ventilation exacerbates lung injury during critical illnesses. In this study we tested whether mechanical ventilation of the alcoholic lung promotes on balance a proinflammatory phenotype favoring ventilator-induced lung injury or an immunosuppressive phenotype favoring ventilator-associated pneumonia. METHODS: Lungs from rats fed an isocaloric diet with or without ethanol (six weeks) were isolated and ventilated ex vivo with a low-volume (protective) or high-volume (injurious) strategy for two hours with or without prior endotoxemia (two hours). In other experiments, rats were subjected to high-volume ventilation in vivo. Airway levels of the proinflammatory cytokines tumor necrosis factor-alpha, macrophage inflammatory protein-2, and interleukin-1beta were determined after mechanical ventilation ex vivo and compared with edematous lung injury after high-volume ventilation in vivo. In parallel, alveolar macrophage phagocytosis of bacteria and secretion of interleukin-12 during ventilation ex vivo and endotoxin-stimulated alveolar macrophage phagocytosis and tumor necrosis factor-alpha secretion in vitro were determined. RESULTS: Ethanol ingestion suppressed the proinflammatory response to injurious mechanical ventilation and did not increase experimental ventilator-induced lung injury. In parallel, ethanol ingestion blunted the innate immune response of alveolar macrophages during injurious ventilation ex vivo and after endotoxin stimulation in vitro. CONCLUSIONS: Ethanol ingestion dampens ventilator-induced inflammation but exacerbates macrophage immune dysfunction. These findings could explain at least in part why alcoholic patients are at increased risk of ventilator-associated pneumonia.

Angiotensin II mediates glutathione depletion, transforming growth factor-beta1 expression, and epithelial barrier dysfunction in the alcoholic rat lung.

Alcohol abuse markedly increases the risk of sepsis-mediated acute lung injury. In a rat model, ethanol ingestion alone (in the absence of any other stress) causes pulmonary glutathione depletion, increased expression of transforming growth factor-beta1 (TGF-beta1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-beta1 into the alveolar space where it can exacerbate epithelial barrier dysfunction and lung edema. Ethanol ingestion activates the renin-angiotensin system, and angiotensin II is capable of inducing oxidative stress and TGF-beta1 expression. We determined that lisinopril, an angiotensin-converting enzyme inhibitor that decreases angiotensin II formation, limited lung glutathione depletion, and treatment with either lisinopril or losartan, a selective angiotensin II type 1 receptor blocker, normalized TGF-beta1 expression. The glutathione precursor procysteine also prevented TGF-beta1 expression, suggesting that TGF-beta1 may be induced indirectly by angiotensin II-mediated oxidative stress and glutathione depletion. Importantly, lisinopril treatment normalized barrier function in alveolar epithelial cell monolayers from ethanol-fed rats, and treatment with either lisinopril or losartan normalized alveolar epithelial barrier function in ethanol-fed rats in vivo, as reflected by lung liquid clearance of an intratracheal saline challenge, even during endotoxemia. In parallel, lisinopril treatment limited TGF-beta1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-beta1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.

Transforming growth factor beta1 expression and activation is increased in the alcoholic rat lung.

Alcohol abuse increases the incidence of acute respiratory distress syndrome more than threefold in patients with septic shock. We have shown that chronic ethanol ingestion in a rat model impairs alveolar epithelial barrier function and enhances lung injury during sepsis. We speculated that transforming growth factor beta(1) (TGFbeta(1)), a pluripotent cytokine implicated in models of epithelial barrier disruption and lung injury, could mediate alveolar epithelial injury in the alcoholic lung. We report that chronic ethanol ingestion (6 weeks) in rats increased both TGFbeta(1) mRNA and protein tissue expression (p < 0.05), but alone did not induce the release of TGFbeta(1) into the alveolar space. However, during endotoxemia, ethanol-fed rats released fivefold more TGFbeta(1) protein (by ELISA, p < 0.05) into the alveolar space than control-fed rats. Furthermore, lung lavage fluid from endotoxemic, ethanol-fed rats had more biologically active TGFbeta(1) protein than control-fed rats (p < 0.05), as reflected by anti-TGFbeta(1) antibody-inhibitable induction of permeability in rat alveolar epithelial monolayers in vitro. We conclude that chronic ethanol ingestion increases lung expression of TGFbeta(1,) which, during endotoxemia, is released and activated in the alveolar space in which it can disrupt the normally tight epithelial barrier. We speculate that this mechanism could contribute to the increased risk of acute respiratory distress syndrome in alcoholic patients.

Granulocyte/macrophage colony-stimulating factor treatment improves alveolar epithelial barrier function in alcoholic rat lung.

Chronic alcohol abuse increases the risk of developing acute lung injury approximately threefold in septic patients, and ethanol ingestion for 6 wk in rats impairs alveolar epithelial barrier function both in vitro and in vivo. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a trophic factor for the alveolar epithelium, and a recent phase II clinical study suggests that GM-CSF therapy decreases sepsis-mediated lung injury. Therefore, we hypothesized that GM-CSF treatment could improve ethanol-mediated defects in the alveolar epithelium during acute stresses such as endotoxemia. In this study, we determined that recombinant rat GM-CSF improved lung liquid clearance (as reflected by lung tissue wet:dry ratios) in ethanol-fed rats anesthetized and then challenged with 2 ml of saline via a tracheostomy tube. Furthermore, GM-CSF treatment improved lung liquid clearance and decreased epithelial protein leak in both control-fed and ethanol-fed rats after 6 h of endotoxemia induced by Salmonella typhimurium lipopolysaccharide given intraperitoneally, but with the greater net effect seen in the ethanol-fed rats. Our previous studies indicate that chronic ethanol ingestion decreases lung liquid clearance by increasing intercellular permeability. Consistent with this, GM-CSF treatment in vitro decreased permeability of alveolar epithelial monolayers derived from both control-fed and ethanol-fed rats. As in the endotoxemia model in vivo, the effect of GM-CSF was most dramatic in the ethanol group. Together, these results indicate that GM-CSF treatment has previously unrecognized effects in promoting alveolar epithelial barrier integrity and that these salutary effects may be particularly relevant in the setting of chronic alcohol abuse.

Chronic ethanol ingestion increases expression of the angiotensin II type 2 (AT2) receptor and enhances tumor necrosis factor-alpha- and angiotensin II-induced cytotoxicity via AT2 signaling in rat alveolar epithelial cells.

BACKGROUND: Alcohol abuse increases the risk of acute lung injury in critically ill patients. We have shown that alveolar epithelial cell (AEC) apoptosis in response to inflammatory mediators, including tumor necrosis factor-alpha (TNF-alpha), parallels endotoxin-mediated acute lung injury in ethanol-fed rats. Although angiotensin II mediates TNF-alpha-induced apoptosis of AECs in vitro, its role in ethanol-mediated susceptibility to AEC apoptosis is unknown. METHODS: Adult male rats were fed the Lieber-DeCarli diet for 6 weeks. AECs were isolated, and TNF-alpha- and angiotensin II-induced cytotoxicity (by terminal transferase-mediated dUTP nick end labeling staining) was determined with or without the addition of the angiotensin-converting enzyme inhibitor (lisinopril) or a selective blocker of the angiotensin II type 1 receptor (AT(1)) or type 2 receptor (AT(2)). Finally, the relative expression of the AT(1) and AT(2) receptors in AECs was determined by Western blot analysis. RESULTS: TNF-alpha-induced cytotoxicity, but not angiotensin II-induced cytotoxicity, was prevented by lisinopril, indicating that de novo angiotensin II synthesis is required for TNF-alpha-induced apoptosis in these cells. Both TNF-alpha- and angiotensin II-induced cytotoxicity in AECs from control-fed and ethanol-fed rats were inhibited by the selective AT(2) blocker, PD123319, but not by the selective AT(1) blocker, losartan. In parallel, ethanol ingestion doubled AT(2) expression in AECs (by Western blot) but had no significant effect on AT(1) receptor expression. CONCLUSIONS: Chronic ethanol ingestion increases AT(2) expression in the alveolar epithelium and enhances TNF-alpha- and angiotensin II-induced cytotoxicity, both of which act via AT(2). Together, these findings suggest that selective AT(2) receptor inhibition could limit the development of acute lung injury in alcoholic patients.

Glutathione replacement preserves the functional surfactant phospholipid pool size and decreases sepsis-mediated lung dysfunction in ethanol-fed rats.

BACKGROUND: Alcohol abuse increases the incidence of acute respiratory distress syndrome (ARDS). Previous evidence from our laboratory links ethanol-mediated glutathione depletion to impaired surfactant production by alveolar epithelial cells in vitro and to endotoxin-mediated edematous injury in isolated lungs ex vivo. ARDS patients have an imbalance between the inactive small aggregate (SA) and the bioactive large aggregate (LA) forms of surfactant phospholipid (as reflected by increased SA/LA ratios). Therefore, we hypothesized that ethanol ingestion, via glutathione depletion, could alter surfactant phospholipid distribution between LA and SA forms and thereby exacerbate sepsis-mediated lung dysfunction in vivo. METHODS: Rats fed an isocaloric diet with or without ethanol (36% total calories) for 6 weeks were made septic via cecal ligation and perforation. Some ethanol-fed rats had their diets supplemented with the glutathione precursor procysteine (>L-2-oxothiaxolidine-4-carboxylate). Sepsis physiology was assessed by determining respiratory rates, arterial blood pressures, and plasma lactate levels, and lung dysfunction was assessed by determining lung lavage fluid protein levels (index of alveolar endothelial/epithelial barrier disruption), arterial hypoxemia (index of impaired gas exchange) and surfactant phospholipid SA and LA fractions (index of the alveolar epithelium's ability to maintain a functional surfactant pool during sepsis). RESULTS: Ethanol ingestion decreased (p< 0.05) lung lavage fluid glutathione levels, and this defect was prevented by procysteine. Although ethanol ingestion had no effect (p< 0.05) on any of the indices of sepsis, it increased (p< 0.05) lung lavage fluid protein levels, worsened hypoxemia, and decreased the functional (LA) surfactant phospholipid pool after sepsis, all of which was prevented by procysteine. CONCLUSIONS: Ethanol ingestion, via glutathione depletion, increased sepsis-mediated lung dysfunction, and these effects could contribute to the increased risk of ARDS seen in alcoholic patients.