Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Language
Publication year range
1.
bioRxiv ; 2023 Nov 06.
Article in English | MEDLINE | ID: mdl-37986982

ABSTRACT

Lung inflammation, caused by acute exposure to ozone (O3) - one of the six criteria air pollutants - is a significant source of morbidity in susceptible individuals. Alveolar macrophages (AMØs) are the most abundant immune cells in the normal lung and their number increases following O3 exposure. However, the role of AMØs in promoting or limiting O3-induced lung inflammation has not been clearly defined. Here, we used a mouse model of acute O3 exposure, lineage tracing, genetic knockouts, and data from O3-exposed human volunteers to define the role and ontogeny of AMØs during acute O3 exposure. Lineage tracing experiments showed that 12, 24, and 72 h after exposure to O3 (2 ppm) for 3h all AMØs were tissue-resident origin. Similarly, in humans exposed to FA and O3 (200 ppb) for 135 minutes, we did not observe ~21h post-exposure an increase in monocyte-derived AMØs by flow cytometry. Highlighting a role for tissue-resident AMØs, we demonstrate that depletion of tissue-resident AMØs with clodronate-loaded liposomes led to persistence of neutrophils in the alveolar space after O3 exposure, suggesting that impaired neutrophil clearance (i.e., efferocytosis) leads to prolonged lung inflammation. Moreover, depletion of tissue-resident AMØ demonstrated reduced clearance of intratracheally instilled apoptotic Jurkat cells, consistent with reduced efferocytosis. Genetic ablation of MerTK - a key receptor involved in efferocytosis - also resulted in impaired clearance of apoptotic neutrophils followed O3 exposure. Overall, these findings underscore the pivotal role of tissue-resident AMØs in resolving O3-induced inflammation via MerTK-mediated efferocytosis.

2.
Int J Tuberc Lung Dis ; 22(1): 112-118, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29297435

ABSTRACT

SETTING: Community of Eldoret, Kenya. OBJECTIVE: To test the performance of three commonly used spirometry prediction equations in a healthy Kenyan population. DESIGN: Cross-sectional assessment of healthy adults in Eldoret. RESULTS: Of the 331 subjects enrolled in the study, 282 subjects aged 18-85 years (45% males, 55% females) produced high-quality spirograms. Lung function predictions were made using the Global Lung Initiative 2012 (GLI 2012) prediction equations for African Americans, the National Health and Nutrition Examination Survey III (NHANES III) prediction equations for African Americans, and the Crapo prediction equation. Bland-Altman analyses were performed to measure the agreement between observed and predicted spirometry parameters. Overall, the GLI 2012 and NHANES equations for African Americans performed similarly for forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), significantly overestimating FVC while accurately predicting observed FEV1 values. CONCLUSION: The study brings into question the utility of three major spirometry prediction equations in a Kenyan population. The significant overestimation of FVC by the best-performing equations despite accurate prediction of FEV1 suggests poor performance of these equations in our population.


Subject(s)
Forced Expiratory Volume/physiology , Respiratory Function Tests/methods , Spirometry/methods , Vital Capacity/physiology , Adolescent , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Kenya , Male , Middle Aged , Reference Values , Young Adult
3.
Clin Exp Allergy ; 47(2): 190-199, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27562295

ABSTRACT

BACKGROUND: Asthma is associated with reduced systemic levels of l-arginine and increased asymmetric dimethylarginine (ADMA). This imbalance leads to nitric oxide synthase (NOS) uncoupling with reduced nitric oxide (NO) formation and greater oxidative and nitrosative stress. Whether this imbalance also occurs in bronchial epitheliumof asthmatics is unknown. OBJECTIVES: We used primary human bronchial epithelial cells (HBECs) from asthmatics and healthy controls to evaluate: (i) ADMA-mediated NOS uncoupling reduces epithelial production of NO and increases oxygen and nitrogen reactive species, and (ii) l-citrulline can reverse this mechanism by recoupling NOS, restoring NO production and reducing oxidative and nitrosative stress. RESULTS: In HBECsIL-13 and INFγ stimulated NOS2 and increased NOx levels. The addition of ADMA reduced NOx and increased H2 O2 levels (p<0.001). Treatment with l-citrulline (800, 1600 µm) rescued NOx when the l-arginine media concentration was 25 µm but failed to do so with higher concentrations (100 µm). Under reduced l-arginine media conditions, HBECs treated with l-citrulline increased the levels of argininosuccinate, an enzyme that metabolizes l-citrulline to l-arginine. l-citrulline prevented the ADMA-mediated increase in nitrotyrosine in HBECs in cells from asthmatics and controls. CONCLUSIONS AND CLINICAL RELEVANCE: Increasing ADMA reduces NO formation and increases oxidative and nitrosative stress in airway epithelial cells. l-citrulline supplementation restores NO formation, while preventing nitrosative stress. These results, suggest that l-citrulline supplementation may indeed be a powerful approach to restore airway NO production and may have a therapeutic potential in diseases in which there is a defective production of NO.


Subject(s)
Arginine/analogs & derivatives , Citrulline/pharmacology , Nitric Oxide/metabolism , Nitrosative Stress/drug effects , Oxidation-Reduction/drug effects , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Adult , Arginine/pharmacology , Asthma/metabolism , Asthma/physiopathology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Female , Humans , Hydrogen Peroxide , Male , Middle Aged , Nitric Oxide Synthase/metabolism , Respiratory Function Tests , Young Adult
4.
Semin Respir Crit Care Med ; 21(3): 223-32, 2000.
Article in English | MEDLINE | ID: mdl-16088735

ABSTRACT

Despite recent advances in technology, the mortality rate for patients suffering from adult respiratory distress syndrome remains in the range of 40-50%. This high mortality rate may be in part related to complications from ventilator management, such as ventilator-induced lung injury. In these patients, adjunct therapies aiming at ameliorating ventilator-induced lung injury are being developed. This article discusses the rationale for use of pharmacologic adjunct therapies, including inhaled nitric oxide, surfactant replacement therapy, antioxidants, prostaglandins, and corticosteroids, in patients with acute lung injury, and reviews the effectiveness of these agents in human clinical trials to date.

5.
Ann Thorac Surg ; 67(3): 851-2, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10215250

ABSTRACT

A case of malignant melanoma presenting as a mediastinal mass without an extrathoracic primary is reported. Microscopically the tumor appeared consistent with malignant melanoma, with the presence of focal melanin pigment in large epithelioid cells. Fontana stain confirmed the presence of melanin pigment. Immunohistochemical staining further suggested melanoma, with the tumor cells expressing a HMB45+, S100+ and cytokeratin-phenotype. Electron microscopy showed an abundance of melanosomes confirming the diagnosis of malignant melanoma.


Subject(s)
Mediastinal Neoplasms/diagnosis , Melanoma/diagnosis , Aged , Female , Humans , Immunohistochemistry , Mediastinal Neoplasms/chemistry , Mediastinal Neoplasms/diagnostic imaging , Mediastinal Neoplasms/pathology , Melanoma/chemistry , Melanoma/diagnostic imaging , Melanoma/pathology , Radiography
6.
Am J Physiol ; 275(1): L96-102, 1998 07.
Article in English | MEDLINE | ID: mdl-9688940

ABSTRACT

L-Arginine can be metabolized by nitric oxide (NO) synthase (NOS) to produce NO or by arginase to produce urea and L-ornithine. In the liver, arginase (the AI isoform) is a key enzyme in the urea cycle. In extrahepatic organs including the lung, the function of arginase (the AII isoform) is less clear. Because we found that lung AII was upregulated during 100% O2 exposure in preliminary experiments, we sought to characterize expression of the arginase isoforms and inducible NOS and to assess the functions of arginase in hyperoxic lung injury. Male Sprague-Dawley rats were exposed to 100% O2 for 60 h. Protein expression of AI and AII and their cellular distribution were determined. The activities of arginase and NOS were also measured. Expression of arginase was correlated with that of ornithine decarboxylase, a biochemical marker for tissue repair, in a separate group of rats allowed to recover in room air for 48 h. We found by Western blot analyses that both AI and AII proteins were upregulated after 60 h of hyperoxic exposure (403 and 88% increases by densitometry, respectively) and, like ornithine decarboxylase, remained elevated during the recovery phase. Arginase activity increased by 37%. Immunostaining showed that increases in AI and AII were mainly in the peribronchial and perivascular connective tissues. NOS activity was unchanged and inducible NOS was not induced, but the level of nitrogen oxides in the lung decreased by 67%. Our study showed in vivo induction of arginase isoforms during hyperoxia. The strong expression of arginase in the connective tissues suggests that the function of pulmonary arginase may be linked to connective tissue elements, e.g., fibroblasts, during lung injury and recovery.


Subject(s)
Arginase/biosynthesis , Hyperoxia/enzymology , Isoenzymes/biosynthesis , Lung/enzymology , Nitric Oxide Synthase/biosynthesis , Animals , Enzyme Induction , Hyperoxia/physiopathology , Immunohistochemistry , Lung/physiology , Lung/physiopathology , Male , Nitric Oxide Synthase Type II , Nitrogen Oxides/metabolism , Rats , Rats, Sprague-Dawley
7.
Shock ; 9(4): 304-9, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9565260

ABSTRACT

The intercellular adhesion molecule (ICAM)-1 is expressed constitutively in normal lungs and increased in pulmonary inflammation. Whether increased ICAM-1 expression in the lung contributes to neutrophil sequestration during lung inflammation in sepsis is unclear. We tested this hypothesis in mice after systemic sepsis from cecal ligation and puncture (CLP). ICAM-1 expression in mouse CLP lung tissue was found to increase with time. The time course of lung ICAM-1 up-regulation correlated with increases in lung myeloperoxidase (MPO) activity and neutrophil sequestration by light microscopy. The monoclonal IgG2b rat anti-mouse antibody, an anti-ICAM-1 antibody (YN1/1.7), administered intravenously at doses of 3, 10, or 30 mg/kg, however, did not decrease the lung MPO levels compared with nonimmune rat IgG. In support of these findings, lung MPO content in ICAM-1-deficient mice that underwent CLP was significantly higher than similarly treated ICAM-1-sufficient mice. Our results suggest that neutrophil sequestration in the mouse lung after CLP is not dependent on ICAM-1.


Subject(s)
Intercellular Adhesion Molecule-1/physiology , Lung/physiopathology , Neutrophils/physiology , Sepsis/physiopathology , Animals , Antibodies/pharmacology , Cecum/microbiology , Immunoglobulin G/pharmacology , Inflammation , Intercellular Adhesion Molecule-1/biosynthesis , Intercellular Adhesion Molecule-1/genetics , Lung/blood supply , Lung/pathology , Male , Mice , Mice, Inbred BALB C , Microscopy, Immunoelectron , Neutrophils/pathology , Neutrophils/ultrastructure , Peroxidase/metabolism , Rats , Sepsis/pathology
8.
Am J Respir Crit Care Med ; 157(3 Pt 1): 938-49, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9517615

ABSTRACT

Recruitment of polymorphonuclear leukocytes (PMN) through upregulation of cellular adhesion molecules is a proposed mechanism of injury in sepsis and acute respiratory distress syndrome (ARDS). We hypothesized that pretreatment of baboons with a monoclonal antibody to human E- and L-selectin (EL-246) during sepsis would decrease PMN influx into tissues and result in less organ injury during gram-negative sepsis. We studied 14 anesthetized, ventilated adult baboons; six animals received 1 mg/kg of EL-246 before infusion of an LD100 of live Escherichia coli and six received the E. coli infusion without antibody therapy. Two other animals received 1 mg/kg of EL-246 intravenously without an infusion of bacteria. Intermittent measurements were made of circulatory pressures, cardiac output, urine output, arterial blood gases, ventilation:perfusion ratio (VA/Q), and hematologic status. The experiments were ended at 48 h or at the time of death. Tissues were harvested for pathology and biochemical measurements. The E. coli infusions were associated with a hyperdynamic state, pulmonary hypertension, systemic hypotension, decreased urine output (UOP), and metabolic acidosis. The antibody partly blocked PMN migration, but there were few significant physiologic or biochemical differences between the EL-246-treated and untreated animals. In the antibody-treated animals, UOP was decreased, metabolic acidosis was worsened, and median survival time was decreased significantly. We conclude that treatment with an antibody to E- and L-selectin in gram-negative sepsis does not improve gas exchange or protect against lung injury, and is associated with decreased survival time in primates.


Subject(s)
Antibodies, Monoclonal/therapeutic use , E-Selectin/immunology , Escherichia coli Infections/complications , L-Selectin/immunology , Respiratory Distress Syndrome/prevention & control , Sepsis/complications , Acidosis/microbiology , Animals , Antibodies, Monoclonal/administration & dosage , Blood Pressure , Carbon Dioxide/blood , Cardiac Output , Cell Adhesion Molecules/immunology , Chemotaxis, Leukocyte/immunology , Humans , Hypertension, Pulmonary/microbiology , Hypotension/microbiology , Injections, Intravenous , Male , Neutrophil Activation , Neutrophils/immunology , Oxygen/blood , Papio , Pulmonary Gas Exchange , Respiration, Artificial , Respiratory Distress Syndrome/microbiology , Survival Rate , Up-Regulation , Urine , Ventilation-Perfusion Ratio
SELECTION OF CITATIONS
SEARCH DETAIL
...