Chromoplectic TPM3-ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRß fusions and may benefit from targeted therapy. PATIENT AND METHODS: We sought to understand the genomic abnormalities of a patient who presented for management of metastatic IMT after progression of disease on crizotinib and a significant and durable partial response to the more potent ALK inhibitor ceritinib. RESULTS: The residual IMT was resected based on the recommendations of a multidisciplinary tumor sarcoma tumor board and analyzed by whole-genome mate pair sequencing. Analysis of the residual, resected tumor identified a chromoplectic TPM3-ALK rearrangement that involved many other known oncogenes and was confirmed by rtPCR. CONCLUSIONS: In our analysis of the treatment-resistant, residual IMT, we identified a complex pattern of genetic rearrangements consistent with chromoplexy. Although it is difficult to know for certain if these chromoplectic rearrangements preceded treatment, their presence suggests that chromoplexy has a role in the oncogenesis of IMTs. Furthermore, this patient's remarkable response suggests that ceritinib should be considered as an option after progression on crizotinib for patients with metastatic or unresectable IMT and ALK mutations.

Pulmonary manifestations of immunoglobulin G4-related sclerosing disease.

Immunoglobulin (Ig)G4-related sclerosing disease (ISD) (also called IgG4-related systemic disease, IgG4-related disease or hyper-IgG4 disease) is a recently described systemic fibroinflammatory disease associated with elevated circulating levels of IgG4. Although initial descriptions of this disorder focused on its pancreatic presentation (autoimmune pancreatitis), it has become apparent that ISD is a systemic disease with many facets. The lesion of ISD is characterised by lymphoplasmacytic inflammation, fibrosis, phlebitis and increased numbers of IgG4-positive plasma cells. The disease can either be localised to one or two organs, or be present with diffuse multi-organ disease. Furthermore, lesions in different organs can present simultaneously or metachronously. In the thorax, lesions associated with ISD have been described in the lung parenchyma, airways and pleura, as well as the mediastinum. Data published to date suggest that ISD may account for a portion of various fibroinflammatory conditions of unknown cause encountered in the chest, including inflammatory pseudotumours, idiopathic interstitial pneumonias, fibrosing mediastinitis, inflammatory pleural lesions and, occasionally, airway disease. Some aspects of pulmonary manifestations attributed to ISD remain controversial and additional studies are needed to clarify the relationship along with the increasing relevance of this disorder to pulmonary medicine.

Haemosiderin-laden macrophages in the bronchoalveolar lavage fluid of patients with diffuse alveolar damage.

Quantification of haemosiderin-laden macrophages in bronchoalveolar lavage fluid (BALF) has been used to diagnose diffuse alveolar haemorrhage (DAH) but has not been assessed in patients with diffuse alveolar damage (DAD). The present study analysed BALF obtained from 21 patients with DAD diagnosed by surgical lung biopsy. The median age of 21 patients with DAD was 68 yrs (range 18-79 yrs); 14 (67%) were male and 12 (57%) were immunocompromised. The median proportion of haemosiderin-laden macrophages in BALF was 5% (range 0-90%), but was >or=20% in seven (33%) patients, fulfilling the commonly used BALF criterion for DAH. There was a trend toward a positive correlation between the percentage of haemosiderin-laden macrophages in BALF and parenchymal haemorrhage assessed semiquantitatively by histopathological analysis. Patients with >or=20% haemosiderin-laden macrophages in BALF showed a significantly increased mortality rate (p = 0.047) compared to those with <20%. In patients with an acute onset of diffuse lung infiltrates and respiratory distress, >or=20% haemosiderin-laden macrophages in BALF can occur with DAD, and is not necessarily diagnostic of DAH. The finding of >or=20% haemosiderin-laden macrophages in BALF is associated with a worse prognosis in patients with DAD.

Autopsy findings in 42 consecutive patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease that commonly results in respiratory failure and death. However, the cause of death in these patients has not previously been fully defined. The current study reviews the clinical records and pathological findings of 42 consecutive patients with IPF who underwent a post mortem at the Mayo Clinic (Rochester, MN, USA) over a 9-yr period, from January 1996 to December 2004. The median (range) age at post mortem for the patients was 74 (46-98 yrs) yrs, which included 25 (60%) males. A total of 31 (74%) patients died in the hospital. The immediate causes of death were reported as: respiratory (64%), cardiovascular (21%), or noncardiopulmonary (14%). Acute exacerbation of IPF was the most common immediate cause of death (29%). Pneumonia, aspiration and drug-induced lung disease were identified as other causes of respiratory death. Evidence of pulmonary hypertension was present in the post mortem of 19 (45%) patients and was the immediate cause of death in two of these patients. The immediate cause of death was clinically unsuspected in five (12%) patients and IPF was diagnosed post mortem in nine (21%) patients. The majority of patients with idiopathic pulmonary fibrosis who had undergone a post mortem were found to have died from respiratory causes. Acute exacerbation of idiopathic pulmonary fibrosis was found to be the most common cause of death whilst death from the gradual progression of idiopathic pulmonary fibrosis was found to be less common.

Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo.

Keratinocyte growth factor (KGF) administered as a single intratracheal injection causes a prominent dose-dependent proliferation of type II alveolar epithelial cells in the lungs of adult rats. The increase in mitotically active alveolar cells histologically appears as a micropapillary epithelial cell hyperplasia after 2 d and peaks after 3 d in the form of monolayers of cuboidal epithelial cells lining alveolar septae. Proliferating cell nuclear antigen immunohistochemistry confirmed the profound proliferative response induced by KGF. The hyperplastic alveolar lining cells contain immunoreactive surfactant protein B and are ultrastructurally noted to contain lamellar inclusions characteristic of surfactant-producing type II pneumocytes. Mild focal bronchiolar epithelial hyperplasia is noted but is much less striking than the proliferation of type II pneumocytes. Large airways are unaffected by KGF. Daily intravenous injection of KGF is also able to cause pneumocyte proliferation. The normal adult rat lung constitutively expresses both KGF and KGF receptor mRNA, suggesting that endogenous KGF may be implicated in the paracrine regulation of the growth of pneumocytes. In conclusion, KGF rapidly and specifically induces proliferation and differentiation of type II pneumocytes in the normal adult lung.

Pulmonary artery sarcoma mimicking pulmonary embolism: a case series.

BACKGROUND: Pulmonary artery sarcoma (PAS) is a rare malignant neoplasm with an aggressive behavior and often difficult to distinguish from pulmonary thromboembolic disease. AIM: To assess the demographic, clinical, and radiological characteristics of PAS and clinical course. DESIGN AND METHODS: We retrospectively identified and analyzed all patients with PAS seen at Mayo Clinic in Rochester, Minnesota, between January 1, 1996 and July 31, 2015. RESULTS: Of nine patients (5 women and 4 men; median age 55 years [range, 24-74 years]), eight were diagnosed while alive with surgical ( n = 6) or catheter-based endovascular biopsy ( n = 2); the remaining patient was diagnosed at postmortem examination. All tumors manifested on CT as filling defect in the main, right or left pulmonary artery and were not associated with peripheral filling defects in seven patients. Seven patients were initially treated with anticoagulant therapy for presumed PE; two patients were suspected to have tumor based on constrictive or expanding effect seen on CT. Five patients died after a mean duration of 2.1 years (10 months-4.25 years) after diagnosis. Two patients are alive with recurrence and metastases of the disease 23 and 27 months after diagnosis, respectively; one remaining patient is alive and disease-free 116 months after diagnosis. CONCLUSIONS: Although PAS is associated with a poor prognosis, long-term survival is possible and can be improved by early diagnosis and prompt surgical resection. Atypical appearance on CT including central mass-like lesion without peripheral emboli and constrictive or expanding effect should raise suspicion of PAS.

Growth pattern-based grading of pulmonary adenocarcinoma-Analysis of 534 cases with comparison between observers and survival analysis.

OBJECTIVES: The 2015 WHO classification of pulmonary adenocarcinoma recommends recording observed architectural growth patterns in 5% increments for resected tumors, and determining the predominant growth pattern, which seems to be prognostic. There is debate over the best way to implement pattern-based grading, and whether such systems are reproducible. MATERIALS AND METHODS: 534 resected adenocarcinomas were reviewed by 2 pulmonary pathologists to determine predominant pattern and percentages of all observed patterns. Three different grading schemes were applied based on predicted prognosis scores: score 1 (lepidic), score 2 (acinar/papillary), and score 3 (solid/micropapillary/cribriform). Mucinous tumors were separately evaluated as both scores 2 and 3 since their prognosis is more ambiguous. The first grading scheme used the score of the predominant pattern; the second used the worst observed pattern score; and the third scored tumors with ≥80% lepidic growth as 1, tumors with ≥20% of any score 3 pattern(s) as 3, and all remaining as 2. RESULTS: The predominant pattern assigned by each observer was an exact match in 51.7% of cases, a "close match" in 27.3% (same prognosis score), and a mismatch in 21%. Predominant pattern determined by both observers showed significant stratification of overall and progression-free survival (OS and PFS, respectively). All 3 grading schemes showed a significant difference in OS and PFS determined by both observers; but the worst score scheme provided suboptimal results, likely due to a very small score 1 group, and this scheme did not maintain significance on multivariable analysis. Survival differences for all grading schemes maintained significance whether mucinous was considered score 2 or 3, but mucinous tumors trended towards poor survival. CONCLUSION: Pattern-based grading has prognostic significance in pulmonary adenocarcinoma. Interobserver variation is present, but two observers were able to predict significant differences in OS and PFS using various pattern-based grading schemes.

Immunosuppressive therapy versus alternative donor hematopoietic stem cell transplantation for children with severe aplastic anemia who lack an HLA-matched familial donor.

We compared the outcomes of immunosuppressive treatment (IST) with those of alternative donor hematopoietic stem cell transplantation (HSCT) in children and adolescents with severe aplastic anemia (SAA). The medical records of 42 patients with SAA who received frontline IST (N=19) or frontline HSCT with an alternative donor (N=23) between 1998 and 2012 were analyzed retrospectively. Six patients responded in the frontline IST group, whereas 11 underwent salvage HSCT after IST failure. Twenty-one of 23 patients who underwent frontline HSCT survived without treatment failure. The estimated failure-free survival rate of the frontline HSCT group was higher than that of the frontline IST group (91.3% vs 30.7% respectively, P<0.001). Six of 11 patients who underwent salvage HSCT experienced event-free survival (EFS). The estimated EFS of the frontline HSCT group was higher than that of the salvage HSCT group (91.3% vs 50.9% respectively, P=0.015). The outcome of alternative donor HSCT was better than commonly reported rates, especially in patients who underwent frontline HSCT. These results suggest that frontline alternative donor HSCT may be a better treatment option than IST for children and adolescents with SAA who lack a human leukocyte Ag-matched familial donor.

A Single-Institution Experience in Percutaneous Image-Guided Biopsy of Malignant Pleural Mesothelioma.

PURPOSE: Mesothelioma has been considered a difficult pathologic diagnosis to achieve via image-guided core needle biopsy. The purpose of this study was to assess the diagnostic sensitivity of percutaneous image-guided biopsy for diagnosis of pleural mesothelioma. MATERIALS AND METHODS: Retrospective review was performed to identify patients with a confirmed diagnosis of pleural mesothelioma and who underwent image-guided needle biopsy between January 1, 2002, and January 1, 2016. Thirty-two patients with pleural mesothelioma were identified and included for analysis in 33 image-guided biopsy procedures. Patient, procedural, and pathologic characteristics were recorded. Complications were characterized via standardized nomenclature [Common Terminology for Clinically Adverse Events (CTCAE)]. RESULTS: Percutaneous image-guided biopsy was associated with an overall sensitivity of 81%. No CTCAE clinically significant complications were observed. No image-guided procedures were complicated by pneumothorax or necessitated chest tube placement. No patients had tumor seeding of the biopsy tract. CONCLUSION: Percutaneous image-guided biopsy can achieve high sensitivity for pathologic diagnosis of pleural mesothelioma with a low procedural complication rate, potentially obviating need for surgical biopsy.

Keratinocyte growth factor ameliorates cyclophosphamide-induced ulcerative hemorrhagic cystitis.

To determine whether keratinocyte growth factor (KGF), an epithelial and urothelial growth factor, ameliorates cyclophosphamide (CP)-induced cystitis in rats, KGF (5 mg/kg) was injected in rats as a single i.v. injection 24 h prior to i.p. injection of CP (200 mg/kg). Bladders were evaluated histologically 48 h after CP injection, and KGF pretreatment was found to almost completely prevent CP-induced ulcerative hemorrhagic cystitis. Urinary KGF levels were measured by ELISA, and KGF was found to be undetectable in control urine, but it was found to appear in the urine of KGF-treated rats at 8 h, with a peak concentration of approximately 10 ng/ml. Bilateral nephrectomy did not diminish the proliferative effect of KGF on urothelium, suggesting that the contribution of urinary KGF to urothelial proliferation is insignificant. In conclusion, systemic administration of KGF is protective against CP-induced cystitis. Although KGF appears in the urine, urinary KGF is not necessary for the proliferative action of KGF on urothelium.

Development of an optimized Compton suppression gamma-ray spectrometric system using Monte Carlo simulation.

We have chosen to establish the Compton Suppression Spectrometer (CSS) for low activity environmental samples with a high purity germanium (HPGe) primary detector and a removable plug-in detector (NaI(Tl)) surrounded with a cylindrical annulus guard detector (NaI(Tl)). Monte Carlo simulation with PENELOPE (PENetration and Energy LOss of Positrons and Electrons) is used to determine the optimal geometry of the CSS. To verify a correlation between experiment and simulation, the energy distribution of (137)Cs and (60)Co point sources is measured and simulated for each condition. The CSS parameters are studied to determine optimal detector geometry and Compton Suppression Factor (CSF). The timing resolution of the CSS was found to be 44ns (FWHM), which is an outstanding result in the semiconductor-based gamma-ray spectrometry. All measured values of CSF agree within 5% with the values obtained from the simulation. The optimum geometry and CSF values are discussed.

Meningioma-like tumor of the skin. An ultrastructural and immunohistochemical study.

Three unusual cutaneous tumors are described along with ultrastructural and immunohistochemical studies. All lesions were asymptomatic red-brown papulonodules. Light microscopic examination revealed a whorled configuration of spindle-shaped cells, some concentrically arranged around blood vessels. Immunohistochemical panels exhibited positive staining only with antibody to vimentin and negative staining with antibodies against S-100 protein, muscle markers, cytokeratin, epithelial membrane antigen, Leu 7, type IV collagen, and factor XIIIa, ruling out obvious nevomelanocytic, nerve sheath, meningothelial, smooth muscle, and perithelial differentiation. Electron microscopic examination demonstrated cells producing poorly formed collagen fibrils, sparse collagen fibers, and possessing occasional ill-defined intercellular junctions between their elongated cell processes. This rare tumor is considered to be either an immature fibrohistiocytic or possibly a nerve sheath neoplasm with striking similarities to so-called canine hemangiopericytoma. Because the prominent whorled pattern was reminiscent of meningioma, the lesion was referred to as meningioma-like tumor of the skin.

Effects of early and delayed wound excision on pulmonary leukosequestration and neutrophil respiratory burst activity in burned mice.

BACKGROUND: Tissue myeloperoxidase (MPO) is a marker of neutrophil (PMN) accumulation in tissues (leukosequestration). We measured MPO in the livers, guts, and lungs of mice after burn injury and studied the additive effect of burn excision on lung MPO. Lung histologic characteristics were also examined. PMN respiratory activity was assessed by measuring intracellular H2O2 content. METHODS: Mice received 32% total body surface area (TBSA) burns; some underwent burn excision followed by wound closure with allograft skin, either immediately or 48 hours after burn. Tissue MPO was measured by a colormetric assay, and intracellular H2O2 was quantified by flow cytometry. RESULTS: MPO was elevated in lungs 8 to 24 hours after burn (p < 0.05) but not in the liver or ileum. Other burned mice received either immediate or 48-hour-delayed wound excision and allografting. In controls a similar-size area was excised and grafted with normal or burned skin. Burned animals had increased lung MPO compared with nonburned animals (p < 0.05). Highest lung MPO levels were seen after burn/immediate excision (p < 0.001). Lung MPO levels were not different comparing unburned mice undergoing skin excision and grafting with either nonburned or burned skin. When burn excision was delayed 48 hours, lung MPO was increased moderately (p < 0.05) but remained far below levels in mice that were excised immediately after burn. PMN influx into lung tissues was confirmed by histologic examination. PMN H2O2 production was increased in burned mice and was additionally increased after immediate wound excision. CONCLUSIONS: Although burn injury produces pulmonary leukosequestration, the phenomenon is unrelated to local effects of burned skin. In this experimental model immediate postburn wound excision increased pulmonary leukosequestration to higher levels than after burn injury alone, and intracellular H2O2 content also increased. Pulmonary leukosequestration may predispose to lung injury, possibly limiting the benefits of wound excision performed extremely early postburn.

Clinical course of human epithelial-type malignant pleural mesothelioma replicated in an orthotopic-transplant nude mouse model.

Malignant pleural mesothelioma is an aggressive tumor that is essentially unresponsive to standard medical and surgical therapies. Little is actually known about its biologic response to therapeutic interventions, in part because of a lack of a "patient-like" animal tumor model. Most experimental models thus far have been derived from inhalation or inoculation of asbestos fibers into animal subjects or by subcutaneous transplantation of human mesothelial cell lines into nude mice. These models are not representative of clinical malignant pleural mesothelioma. In this report, an animal model of human pleural malignant mesothelioma obtained by orthotopic transplantation of intact pleural tumor tissue into athymic nude mice is described. Pleural tumor obtained by thoracolscopy from a patient with epithelial-type malignant pleural mesothelioma was implanted as intact tissue by surgical orthotopic implantation (SOI) into the right pleural cavity of nude mice. Animals were sacrificed when moribund or 6 months after implantation. Tumor growth and regional spread in the mice evaluated at post-mortem examination mimicked the clinical pattern of progression of human disease. Histologic findings and the immunohistochemical profile were similar to those demonstrated on examination of thoracoscopic parietal pleural biopsy specimens and post-mortem examination of the original patient's tumor. This "patient-like" nude mouse model of epithelial-type malignant pleural mesothelioma, phenotypically similar to the original human tumor, should facilitate future investigation of tumorigenesis and metastatic potential of this neoplasm. The model should serve as a basis for assessing the impact of experimental and existing therapy on malignant mesothelioma.

Detecting pulmonary abnormalities on magnetic resonance images in patients with usual interstitial pneumonitis: effect of varying window settings and gadopentetate dimeglumine.

RATIONALE AND OBJECTIVES: We examined the effect of varying window settings and contrast enhancement on detecting pulmonary abnormalities on magnetic resonance (MR) images in patients with usual interstitial pneumonitis (UIP). METHODS: HRCT scans and MR images from 10 patients with UIP were evaluated. T1-weighted MR images were obtained before and after administration of gadopentetate dimeglumine and were photographed at conventional windows and at windows chosen to increase the conspicuity of the lung parenchyma ("lung windows"). The four MR image configurations were mixed with the high-resolution computed tomography (HRCT) scans of these patients and randomized. Corresponding scan levels in each patient were evaluated conjointly by two thoracic radiologists for the presence of "honeycomb lung," ground-glass opacity, parenchymal bands, and reticular abnormalities. Lung signal intensity in areas containing ground-glass signal intensity was measured on MR images using regions of interest. RESULTS: The administration of gadopentetate dimeglumine significantly improved the detection of honeycomb lung on scans photographed at lung windows, but it did not significantly influence the detection of ground-glass abnormalities. The use of lung windows improved the detection of ground-glass abnormalities for both enhanced and unenhanced scans, but lung windows improved the detection of honeycomb lung only for enhanced scans. All MR image configurations were insensitive compared with HRCT scans for detecting parenchymal bands and reticular abnormalities. There was a good correlation between measured lung signal intensity and visual ground-glass profusion score. CONCLUSION: The visibility of pulmonary abnormalities on MR images of patients with UIP is limited compared with that of HRCT scans. The improved visibility of some parenchymal abnormalities after intravenous administration of gadopentetate dimeglumine and with the use of lung windows is insufficient to warrant their routine use in thoracic MR imaging.

Radiation-induced lung injury in vivo: expression of transforming growth factor-beta precedes fibrosis.

Cytokine release from irradiated cells has been postulated to start soon after irradiation preceding detectable clinical and pathological manifestation of lung injury. The expression of transforming growth factor beta (TGF beta), a fibrogenic and radiation-inducible cytokine, was studied from 1-16 weeks after the 15 and 30 Gray (Gy) of thoracic irradiation to rats. Thoracic irradiation caused an increase in TGF beta protein in bronchoalveolar lavage (BAL) fluid peaking at 3-6 weeks as compared to sham-irradiated control rats. Steady state TGF beta mRNA expression as shown by whole lung northern blot assay paralleled the TGF beta protein expression in BAL fluid. The peak of TGF beta protein increase in BAL fluid between 3 and 6 weeks coincided with the initial influx of inflammatory cells in BAL fluid, but preceded histologically discernable pulmonary fibrosis that was not apparent until 8-10 weeks after irradiation. In conclusion. TGF beta and mRNA and protein upregulation preceded the radiation-induced pulmonary fibrosis, suggesting a pathogenetic role in the development of radiation fibrosis.

The intratracheal administration of endotoxin: X. Dexamethasone downregulates neutrophil emigration and cytokine expression in vivo.

Intratracheal instillation of endotoxin (LPS) causes acute pulmonary inflammation characterized by the accumulation of plasma proteins and leukocytes within the pulmonary airways. The synthetic glucocorticoid dexamethasone 1) inhibits the LPS-initiated vascular leak of plasma proteins into the airspace, 2) inhibits the LPS-initiated emigration of neutrophils and lymphocytes into the airspace in a dose-dependent fashion, and 3) inhibits LPS-initiated mRNA and/or bronchoalveolar lavage protein expression of cytokines (TNF, IL-1 and IL-6) and chemokines (MIP-1 alpha, MIP-2 and MCP-1). In conclusion, dexamethasone inhibits both the vascular and cellular aspects of acute inflammation by downregulation of a broad spectrum of inflammatory cytokines and chemokines.

Keratinocyte growth factor decreases pulmonary edema, transforming growth factor-beta and platelet-derived growth factor-BB expression, and alveolar type II cell loss in bleomycin-induced lung injury.

Keratinocyte growth factor (KGF), a potent growth factor for type II pneumocytes and Clara cells, has been shown to prevent the end-stage pulmonary fibrosis and mortality in a rat model of bleomycin-induced lung injury. In this study, protective effects of KGF were explored during the earlier course of bleomycin-induced lung injury by studying protein exudation in alveolar edema fluids, pulmonary expression of transforming growth factor-beta (TGF beta) and platelet-derived growth factor-BB (PDGF-BB), and changes in type II pneumocytes and Clara cells after i.t. (intratracheal) bleomycin injection following KGF- or saline-pretreatment in rats. Total protein in bronchoalveolar lavage (BAL) fluids after bleomycin injury from KGF-pretreated rats was significantly lower than the levels in saline-pretreated rats. TGF beta protein in BAL fluids which peaked at day 3 after i.t. bleomycin in saline-pretreated lungs was not significantly increased at any time points in KGF-pretreated rats. PDGF-BB protein in whole lung tissues of KGF-pretreated rats also remained near normal throughout the course after i.t. bleomycin, in contrast to the significant increase in saline-pretreated rats. Numbers of type II pneumocytes and Clara cells in KGF-pretreated lungs after a high dose of bleomycin were close to the normal in intact lungs. At the same dose of bleomycin injury, type II pneumocytes in saline-pretreated lungs were markedly decreased, while the number of Clara cells in these rats was relatively preserved as the pre-injury level. In conclusion, KGF prevents bleomycin-induced end-stage pulmonary injury and mortality probably at least partly by decreasing protein-rich pulmonary edema, protein expression of fibrogenic cytokines TGF beta and PDGF-BB, and type II cell loss during the course of lung injury.

Intratracheal administration of endotoxin and cytokines: VIII. LPS induces E-selectin expression; anti-E-selectin and soluble E-selectin inhibit acute inflammation.

E-selectin is an inducible endothelial adhesion molecule that binds neutrophils. E-selectin mRNA is not constitutively detectable in the lungs of rats. Intratracheal injection of LPS induces pulmonary E-selectin mRNA expression at 2-4 h. Intratracheal injection of LPS followed at 2 and 4 h by intravenous injection of mouse F(ab')2 or F(ab') anti-E-selectin monoclonal antibody inhibits the emigration of neutrophils into the bronchoalveolar space at 6 h by 50-70%. TNF and IL-6 bioactivity are not decreased in bronchoalveolar lavage fluid after treatment with anti-E-selectin antibody as compared to controls, suggesting that the anti-E-selectin does not affect the magnitude of the LPS-initiated cytokine cascade. Intratracheal injection of LPS followed at 2 and 4 h by intravenous injection of soluble E-selectin inhibits neutrophilic emigration at 6 h by 64%, suggesting that endogenous soluble E-selectin shed from activated endothelium may play a role in the endogenous down-regulation of acute inflammation. E-selectin-mediated adhesion of neutrophils to endothelium appears crucial to the full development of the acute inflammation response.