interleukin-8 and Pneumonia--Aspiration

This paper's goal is to review the relationship between infections and chronic respiratory disease, with particular reference to periodontal disease. The link between oral diseases in general, periodontal disease, and respiratory disease remains somewhat controversial. However, with cooperation between dentistry and medicine, the nature of the connection between dental and medical pathology can be better defined. An overview of respiratory disease and some of the factors that can contribute to respiratory infection is presented below, with special reference to infections related to aspiration.

Topics: Bacteria; Cough; Deglutition; Humans; Interleukin-8; Lung; Periodontal Diseases; Pneumonia, Aspiration; Pneumonia, Bacterial; Pulmonary Disease, Chronic Obstructive; Respiratory Physiological Phenomena; Respiratory Tract Diseases; Respiratory Tract Infections; Risk Factors; Saliva; Smoking

Pneumonia associated with aspiration of bacterial-laden gastric contents is characterized by Glu-Leu-Arg (ELR)-CXC chemokine (e.g., CXC2L1, CXCL8) expression leading to local neutrophil sequestration. This neutrophil response is designed to be protective, but overly aggressive responses can be pathogenic in themselves. Herein we assessed whether blocking neutrophil responses in a guinea pig model of aspiration pneumonia would foster airway bacterial growth. Guinea pigs (n=5) were challenged intranasally with saline, acidified saline or acidified gastric contents (35mg/kg body weight, pH 2.0) and treated subcutaneously with 250mug/kg of the human ELR-CXC chemokine antagonist CXCL8((3-72))K11R/G31P (G31P) or saline. After 20h the animals' airway inflammatory responses and bacterial burdens were assessed. A loss of vascular integrity was apparent in the lungs of the saline-treated aspiration pneumonia animals (12.07+/-1.3% of the pleural surfaces exhibited hemorrhagic consolidation, 4.6x10(6) RBC/ml bronchoalveolar lavage fluid [BALF]), as was a pulmonary neutrophilia. The BAL fluids contained gram-negative and -positive bacteria (total load, 6.3+/-3.2x10(7) CFU/ml BALF) that are associated with nosocomial infections in humans. The G31P-treatments attenuated the pulmonary vascular complications (2.27+/-0.5% pleural surface hemorrhagic consolidation, 0.46x10(6) RBC/ml BALF), and reduced the pulmonary neutrophilia by >/=86%. The G31P-treatments did not lead to significant changes in the airway bacterial loads (total load, 3.46+/-1.8x10(7) CFU/ml BALF). This data indicates that attenuation of the pulmonary neutrophil response in aspiration pneumonia reduces pathology very significantly but does not reduce the efficiency of pulmonary bacterial clearance.

Topics: Animals; Bacteria; Cell Degranulation; Chemokine CXCL1; Disease Models, Animal; Female; Guinea Pigs; Immunity, Innate; Interleukin-8; Lung; Neutrophil Infiltration; Pneumonia, Aspiration; RNA, Messenger

To investigate the role of apoptosis of pulmonary cells in aspiration induced lung injury in patients with severe brain injury with or without aspiration-induced lung injury.. The Glasgow scale (GCS) of 11 dead patients with severe closed brain injury was 3-8. There 11 cases were divided into aspiration-induced lung injury (AILI) and non-aspiration-induced lung injury (NAILI) groups. The plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) were measured, and the ratio of apoptosis in lung tissue cells was also determined.. The plasma levels of TNF-alpha and IL-8 in NAILI and AILI groups were (2.17+/-0.41)nug/L vs. (3.14+/-0.28)nug/L and (0.42+/-0.05)nug/L vs. (0.91+/-0.08) nug/L (P<0.05) respectively. Lung tissue cell apoptosis ratio was significantly higher in AILI group than NAILI group (P<0.01).. TNF-alpha and IL-8 may induce apoptosis in lung tissues through different signaling pathway. During the early phase of aspiration-induced lung injury complicating severe closed brain injury, apoptosis in cells of lung tissue may play a role in the pathogenes.

Topics: Adult; Apoptosis; Autopsy; Brain Injuries; Female; Humans; In Situ Nick-End Labeling; Interleukin-8; Lung; Male; Pneumonia, Aspiration; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Although prior experimental work has demonstrated that anti-interleukin-8 (anti-IL-8) therapy reduces lung endothelial injury after acid instillation, there is no information regarding the effect of anti-IL-8 on the function of the alveolar epithelial barrier after acid-induced lung injury. Therefore, the primary objective of this study was to determine the effect of acid-induced lung injury on the function of the alveolar epithelium, and secondly to determine whether pretreatment with anti-IL-8 attenuates acid-induced injury to the lung epithelial barrier. Hydrochloric acid (pH = 1.5 in 1/3 normal saline) was instilled into the lungs of anesthetized, ventilated rabbits. Anti-IL-8 monoclonal antibody (2 mg/kg) or saline was given intravenously 5 min before acid instillation. Acid instillation into the distal airspaces caused an increase in the alveolar epithelial permeability to protein and an approximately 50% reduction in net alveolar fluid clearance. Because a decrease in net alveolar fluid clearance could be due to lung endothelial injury and increased fluid flux from the blood into the airspaces, additional experiments were carried out in which pulmonary blood flow was eliminated. In the absence of pulmonary blood flow, acid instillation led to a 50% decrease in net alveolar fluid clearance. Pretreatment with anti-IL-8 antibody significantly reduced the acid-mediated increase in bi-directional transport of protein across the alveolar epithelium and restored alveolar fluid clearance to normal. The results indicate that acid instillation causes injury to the alveolar epithelial barrier that can be distinguished from the injury to the lung endothelium. Furthermore, pretreatment with anti-IL-8 therapy prevents acid-induced alveolar epithelial injury, a finding of potential clinical importance.

Topics: Animals; Antibodies, Monoclonal; Biological Transport, Active; Capillary Permeability; Extravascular Lung Water; Hemodynamics; Hydrochloric Acid; Interleukin-8; Lung; Male; Permeability; Pneumonia, Aspiration; Proteins; Pulmonary Alveoli; Rabbits; Recombinant Proteins; Respiratory Distress Syndrome; Respiratory Mucosa

Topics: Animals; Antibodies, Monoclonal; Bronchoalveolar Lavage Fluid; Capillary Permeability; Chemotaxis, Leukocyte; Disease Models, Animal; Endotoxins; Enzyme-Linked Immunosorbent Assay; Extravascular Lung Water; Humans; Interleukin-8; Leukocyte Count; Neutrophils; Pleurisy; Pneumonia, Aspiration; Rabbits

To define the toxicity of cystic fibrosis transmembrane conductance regulator gene (CFTR) gene therapy with a replication-deficient recombinant adenovirus (Av1Cf2) in a nonhuman primate model, 10(10) plaque forming units (pfu) were instilled directly through a bronchoscope into the right lung of 5 macaques, and a lower dose of 4 x 10(6) pfu was administered to the right lung of 1 macaque. One sham-treated control received phosphate-buffered saline (PBS). The macaques were evaluated sequentially by clinical examination, vital signs, weight, hematology, blood chemistry, chest radiography, pulse oximetry, and bronchoalveolar lavage (BAL) at baseline and 3-28 days post-treatment. After the period of observation, macaques were sacrificed for autopsy and histological examination. The macaques tolerated the experimental therapy clinically with no changes in body temperature, oxygen saturation, heart rate, body weight, or blood pressure. However, 1 macaque with visible evidence of aspiration at the time of initial bronchoscopy developed tachypnea with right lower lobe (RLL) pneumonia on chest radiograph and by histology. There were no changes in Hgb, Wbc, BUN, plasma electrolytes, bilirubin, or hepatic transaminases. In the macaques that received 10(10) pfu, there was a progressive increase in the number of CD8+ lymphocytes in BAL that was maximal at 28 days. Histological examination of the treated lungs of the high-dose macaques at 3 days showed marked peribronchial and perivascular cuffing by inflammatory cells and alveolar accumulation of neutrophils and macrophages. The alveolitis appeared to be resolving at 28 days, although the perivascular and peribronchial aggregates of mononuclear cells were still present. In the high-dose macaques, BAL interleukin-8 (IL-8) was increased at all time points (256-388 pg/ml versus 1-84 pg/ml at baseline and in control), whereas IL-1 beta was increased only at days 21 and 28 (341-852 pg/ml versus 30-92 pg/ml at baseline and in control). There were no increases in BAL cell counts, IL-1 beta or IL-8, and histological changes were mild in the macaque that received 4 x 10(6) pfu. Evaluation for Av1Cf2-derived human CFTR expression using RS-PCR demonstrated expression at 3, 10, and 21, but not 28 days in macaques treated with 10(10) pfu of Av1Cf2. In situ hybridization analysis demonstrated human CFTR mRNA in the alveolar regions of the lobes that received the vector at 10 and 21 days. There was no evidence of expression after tr

Topics: Adenoviridae; Animals; Base Sequence; Bronchoalveolar Lavage Fluid; Cystic Fibrosis Transmembrane Conductance Regulator; Defective Viruses; DNA, Complementary; Female; Genetic Therapy; Genetic Vectors; Hemodynamics; Humans; In Situ Hybridization; Interleukin-1; Interleukin-8; Kidney Function Tests; Liver Function Tests; Lung; Macaca fascicularis; Molecular Sequence Data; Pneumonia, Aspiration; Pneumonia, Viral; Recombinant Fusion Proteins; Respiratory Function Tests; Single-Blind Method; Tissue Distribution; Transfection

Acid aspiration lung injury may be mediated primarily by neutrophils recruited to the lung by acid-induced cytokines. We hypothesized that a major acid-induced cytokine was IL-8 and that a neutralizing anti-rabbit-IL-8 monoclonal antibody (ARIL8.2) would attenuate acid-induced lung injury in rabbits. Hydrochloric acid (pH = 1.5 in 1/3 normal saline) or 1/3 normal saline (4 ml/kg) was instilled into the lungs of ventilated, anesthetized rabbits. The rabbits were studied for 6 or 24 h. In acid-instilled rabbits without the anti-IL-8 monoclonal antibody, severe lung injury developed in the first 6 h; in the long-term experiments, all rabbits died with lung injury between 12 and 14 h. In acid-instilled rabbits given the anti-IL-8 monoclonal antibody (2 mg/kg, intravenously) either as pretreatment (5 min before the acid) or as treatment (1 h after the acid), acid-induced abnormalities in oxygenation and extravascular lung water were prevented and extravascular protein accumulation was reduced by 70%; in the long-term experiments, anti-IL-8 treatment similarly protected lung function throughout the 24-h period. The anti-IL-8 monoclonal antibody also significantly reduced air space neutrophil counts and IL-8 concentrations. This study establishes IL-8 as a critical cytokine for the development of acid-induced lung injury. Neutralization of IL-8 may provide the first useful therapy for this clinically important form of acute lung injury.

Topics: Animals; Capillary Permeability; Hemodynamics; Hydrogen-Ion Concentration; Interleukin-8; Male; Neutrophils; Pneumonia, Aspiration; Rabbits; Tumor Necrosis Factor-alpha