epidermal-growth-factor and Respiratory-Distress-Syndrome

Acute respiratory distress syndrome (ARDS) remains a serious, often fatal, condition, despite progress in modern critical care treatment. Cytokines play important roles in the pathogenesis of the syndrome, although their roles in the evaluation and outcome have not been clearly elucidated yet.. We tested whether serum concentration of epidermal growth factor (EGF), as one of the important inflammatory mediators, changes with time and administration of mechanical ventilation and aminophylline.. Thirty patients [mean (SD): age = 56.6 (17.4) years] with ARDS were enrolled. After diagnosis based on inclusion and exclusion criteria, the patients were intubated and mechanically ventilated. Two hours after ventilation with definite positive end-expiratory pressure (PEEP), aminophylline with a specific dose was started. Serum samples were obtained at five time points of 0, 2, 2.5, 4 and 8 h post-starting PEEP.. Serum EGF concentration decreased after mechanical ventilation with PEEP (P < 0.05). The serum EGF concentrations 8 h after intervention was statistically lower in the low PEEP group than in the high PEEP group. The Acute Physiology and Chronic Health Evaluation (APACHE) Pi score and PaO2/FiO2 improved significantly after 8 h (P < 0.05).. Beneficial effects of mechanical ventilation and aminophylline on APACHE Pi score and PaO2/FiO2 influence serum EGF levels. These findings may have relevance to the development of multisystem organ failure.

Topics: Aminophylline; APACHE; Critical Illness; Epidermal Growth Factor; Female; Humans; Injections, Intravenous; Intensive Care Units; Male; Middle Aged; Outcome Assessment, Health Care; Oxygen; Partial Pressure; Patient Selection; Positive-Pressure Respiration; Respiratory Distress Syndrome; Time Factors

Epidermal growth factor (EGF) is involved in alveolar epithelial repair, lung fluid clearance and inflammation, and is regulated by sex hormones. An unmatched, nested case-control study was conducted to evaluate the associations of EGF variants with acute respiratory distress syndrome (ARDS) and the role of sex on the associations between EGF variants and ARDS. Patients with ARDS risk factors upon intensive care unit admission were enrolled. Cases were 416 Caucasians who developed ARDS and controls were 1,052 Caucasians who did not develop ARDS. Cases were followed for clinical outcomes and 60-day mortality. One functional single nucleotide polymorphism (SNP), rs4444903, and six haplotype-tagging SNPs spanning the entire EGF gene were genotyped. No individual SNP or haplotype was associated with ARDS risk or outcomes in all subjects. Sex-stratified analyses showed opposite effects of EGF variants on ARDS in males versus in females. SNPs rs4444903, rs2298991, rs7692976 and rs4698803, and haplotypes GGCGTC and ATCAAG were associated with ARDS risk in males. No associations were observed in females. Interaction analysis showed that rs4444903, rs2298991, rs7692976 and rs6533485 significantly interacted with sex for ARDS risk. The present study suggests that associations of epidermal growth factor gene variants with acute respiratory distress syndrome risk are modified by sex. The current findings should be replicated in other populations.

Topics: Aged; Case-Control Studies; Epidermal Growth Factor; Female; Genotype; Haplotypes; Humans; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Respiratory Distress Syndrome; Risk; Sex Factors

The bronchial epithelium is an important physical barrier that regulates physiological processes including leukocyte trafficking. The aim of the present study was to elucidate the mechanisms whereby the bronchial epithelium, stimulated by epidermal growth factor (EGF) as part of a response to acute or chronic injury, could activate and chemoattract human neutrophils. Subconfluent human bronchial epithelial (16HBE) cells were stimulated with EGF to mimic the in vivo events after injury. The effect of the resulting EGF-conditioned media (CM) was compared with that of basal-CM with respect to neutrophil activation and chemotaxis. Such findings were then confirmed using primary bronchial epithelial cells (PBECs) from healthy volunteers. EGF-CM from 16HBE cells caused increased expression of CD11b/CD66b and CD62L loss on neutrophils when compared with basal-CM. EGF-CM contained significant neutrophil chemotactic activity involving granulocyte-macrophage colony-stimulating factor and interleukin-8 that was potentiated by leukotriene B(4). This was dependent on neutrophil phosphatidylinositol-3-kinase activation and Akt phosphorylation, with partial regulation by phospholipase D, but not mammalian target of rapamycin. Consistent with these observations, EGF-CM derived from PBECs displayed increased chemotactic activity. The present results suggest that the enhanced chemotactic activity of the epidermal growth factor-conditioned epithelium can enhance neutrophil-mediated immunity during acute injury, while during continued injury and repair, as in chronic asthma, this could contribute to persistent neutrophilic inflammation.

Topics: Bronchi; Cell Line; Chemotaxis, Leukocyte; Culture Media, Conditioned; Epidermal Growth Factor; Epithelial Cells; Humans; Inflammation; Neutrophils; Respiratory Distress Syndrome; Signal Transduction

Biologically active interleukin (IL)-1beta is present in the pulmonary edema fluid obtained from patients with acute lung injury and has been implicated as an important early mediator of nonpulmonary epithelial wound repair. Therefore, we tested the hypothesis that IL-1beta would enhance wound repair in cultured monolayers from rat alveolar epithelial type II cells. IL-1beta (20 ng/ml) increased the rate of in vitro alveolar epithelial repair by 118 +/- 11% compared with that in serum-free medium control cells (P < 0.01). IL-1beta induced cell spreading and migration at the edge of the wound but not proliferation. Neutralizing antibodies to epidermal growth factor (EGF) and transforming growth factor-alpha or inhibition of the EGF receptor by tyrphostin AG-1478 or genistein inhibited IL-1beta-induced alveolar epithelial repair, indicating that IL-1beta enhances in vitro alveolar epithelial repair by an EGF- or transforming growth factor-alpha-dependent mechanism. Moreover, the mitogen-activated protein kinase pathway is involved in IL-1beta-induced alveolar epithelial repair because inhibition of extracellular signal-regulated kinase activation by PD-98059 inhibited IL-1beta-induced alveolar epithelial repair. In conclusion, IL-1beta augments in vitro alveolar epithelial repair, indicating a possible novel role for IL-1beta in the early repair process of the alveolar epithelium in acute lung injury.

Topics: Animals; Enzyme Inhibitors; Epidermal Growth Factor; Epithelial Cells; ErbB Receptors; Flavonoids; In Vitro Techniques; Interleukin-1; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Respiratory Mucosa; Specific Pathogen-Free Organisms; Transforming Growth Factor alpha; Wound Healing