Background: Inhaled endotoxin is known to induce airway inflammation, causing bronchial hyper-reactivity.
Objective: We characterized the response to lipopolysaccharide-inhalation by measuring exhaled nitric oxide (eNO) and inflammatory mediators.
Patients and Methods : A total of 43 adult volunteers (13 asthmatics, 30 healthy controls) inhaled stepwise LPS every 30 min up to a cumulative dose of 100 µg (2.5, 10.5, 42, 45 µg). After each provocation and up to 24 h later, FEV1 was determined; the procedure was stopped when FEV1 declined more than 12.5%. We measured eNO, leucocytes, eosinophils, polymorphonuclear neutrophils (PMNs), C-reactive protein (CrP), lipopolysaccharide binding protein (LBP), eosinophilic cationic protein (ECP), leucotriene B4 (LTB4), thromboxane B2 (TXB2), and body temperature.
Results: Initial eNO values were higher in asthmatics (P < 0.01), but only increased in an asthmatic subgroup. Marked differences were observed in the systemic response to LPS inhalation. Significant increases were found for CrP, LBP, and PMNs. There was no correlation between FEV1 decrease and basal eNO levels.
Conclusions: Inhalation of endotoxin was followed by clinical and laboratory signs of systemic inflammation, with asthmatics responding to the challenge similar as healthy subjects. Bronchial eNO increased only temporarily in asthmatics.
Rylander R., Haglind P., Lundholm M.Endotoxin in cotton dust and respiratory function decrement among cotton workers in an experimental cardroom. Am Rev Respir Dis1985; 131: 209—213.
2.
Smid T., Heederik D., Houba R. et al. Dust- and endotoxin-related respiratory effects in the animal feed industry. Am Rev Respir Dis1992; 146: 1474—1479.
3.
Fearon DT, Locksley RMThe instructive role of innate immunity in the acquired immune response. Science1996; 272: 50—53.
4.
Medzhitov R. , Janeway Jr CA. Innate immunity: impact on the adaptive immune response. Curr Opin Immunol1997; 9: 4—9.
5.
Boehlecke B. , Hazucha M., Alexis NE et al. Low-dose airborne endotoxin exposure enhances bronchial responsiveness to inhaled allergen in atopic asthmatics . J Allergy Clin Immunol2003; 112: 1241—1243.
6.
Rylander R., Bake B., Fischer JJ et al. Pulmonary function and symptoms after inhalation of endotoxin . Am Rev Respir Dis1989; 140: 981—986.
7.
Michel O., Duchateau J., Sergysels R.Effect of inhaled endotoxin on bronchial reactivity in asthmatic and normal subjects. J Appl Physiol1989; 66: 1059—1066.
8.
Michel O., Kips J., Duchateau J. et al. Severity of asthma is related to endotoxin in house dust. Am J Respir Crit Care Med1996; 154: 1641—1646.
9.
Michel O.Role of lipopolysaccharide (LPS) in asthma and other pulmonary conditions . J Endotoxin Res2003; 9: 293—300.
10.
Kline JN, Cowden JD, Hunninghake GW et al. Variable airway responsiveness to inhaled lipopolysaccharide . Am J Respir Crit Care Med1999; 160: 297—303.
11.
Michel O., Nagy AM, Schroeven M. et al. Dose-response relationship to inhaled endotoxin in normal subjects . Am J Respir Crit Care Med1997; 156: 1157—1164.
12.
Michel O., Dentener M., Corazza F. et al. Healthy subjects express differences in clinical responses to inhaled lipopolysaccharide that are related with inflammation and with atopy . J Allergy Clin Immunol2001; 107: 797—804.
13.
Franklin PJ , Stick SM, Le Souef PN et al. Measuring exhaled nitric oxide levels in adults. The importance of atopy and airway responsiveness. Chest2004; 126: 1540—2545.
14.
Ho LP, Wood FT, Robson A. et al. Atopy influences exhaled nitric oxide levels in adult asthmatics . Chest2000; 118: 1327—1331.
15.
Piipari R., Piirila P., Keskinen H. et al. Exhaled nitric oxide in specific challenge tests to assess occupational asthma. Eur Respir J2002; 20: 1532—1537.
16.
Stitt JT, Dubois AB, Douglas JS et al. Exhalation of gaseous nitric oxide by rats in response to endotoxin and its absorption by the lungs. J Appl Physiol1997; 82: 305—316.
Rolla G., Bucca C., Brussino L. et al. Pentoxifylline attenuates LPS-induced bronchial hyperresponsiveness but not the increase in exhaled nitric oxide. Clin Exp Allergy1997; 27: 96—103.
19.
Sundblad BM , Larsson BM, Palmberg L. et al. Exhaled nitric oxide and bronchial responsiveness in healthy subjects exposed to organic dust. Eur Respir J2002; 20: 426—431.
20.
VanderMeer TJ, Menconi MJ, O'Sullivan BP et al. Acute lung injury in endotoxemic pigs: role of leukotriene B4. J Appl Physiol1995 ; 78: 1121—1131.
21.
Uhlig S., Nusing R., von Bethmann A. et al. Cyclooxygenase-2-dependent bronchoconstriction in perfused rat lungs exposed to endotoxin. Mol Med1996; 2: 373—383.
22.
Alving K., Weitzberg E., Lundberg JMIncreased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J1993; 6: 1368—1370.
23.
American Thoracic Society.Recommendations for standardized procedures for the online and offline measurements of exhaled lower respiratory nitric oxide and nasal oxide in adults and children . Am J Respir Crit Care Med1999; 160: 2104—2117.
24.
Wang D., Wei J., Hsu K. et al. Effects of nitric oxide synthase inhibitors on systemic hypotension, cytokines and inducible nitric oxide synthase expression and lung injury following endotoxin administration in rats. J Biomed Sci1999; 6: 28—35.
25.
Okamoto T., Gohil K., Finkelstein EI et al. A multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice. Am J Physiol2004; 286(1): L198—L209.
26.
Lee RP, Wang D., Kao Sju et al. The lung is the major site that produces nitric oxide to induce acute pulmonary edema in endotoxin shock. Clin Exp PharmPhysiol2001; 28: 315—320.
27.
Wesselius LJ , Nelson ME, Bailey K. et al. Rapid lung cytokine accumulation and neutrophil recruitment after lipopolysaccharide inhalation by cigarette smokers and nonsmokers. J Lab Clin Med1997; 129: 106—114.
28.
Toward TJ, Broadley KJAirway reactivity, inflammatory cell influx and nitric oxide in guinea-pig airways after lipopolysaccharide inhalation. Br J Pharmacol2000; 131: 271—281.
29.
Rylander R. , Michel O.Organic dust induced inflammation —role of atopy and TLR-4 and CD14 gene polymorphisms. Am J Ind Med2005; 48: 302—307.
30.
Alba-Loureiro TC, Martins EF, Miyasaka CK et al. Evidence that arachidonic acid derived from neutrophils and prostaglandin E2 are associated with the induction of acute lung inflammation by lipopolysaccharide of Escherichia coli. Inflamm Res2004; 53: 658—663.
31.
von Aulock S., Hermann C., Hartung T.Determination of the eicosanoid response to inflammatory stimuli in whole blood and its pharmacological modulation ex vivo. J Immunol Methods2003; 277: 53—63.
32.
Brass DM, Savov JD, Whitehead GS et al. LPS binding protein is important in the airway response to inhaled endotoxin. J Allergy Clin Immunol2004; 114: 586—592.
33.
Dentener MA , Vreugdenhil Ace, Hoet Phm et al. Production of the acute-phase protein lipopolysaccharide-binding protein by respiratory type II epithelial cells . Am J Respir Cell Mol Biol2000; 23: 146—153.
Michel O., Duchateau J., Plat G. et al. Blood inflammatory response to inhaled endotoxin in normal subjects . Clin Exp Allergy1995; 25: 73—79.
36.
Dubin W., Martin TR, Swoveland P. et al. Asthma and endotoxin: lipopolysaccharide-binding protein and soluble CD14 bronchoalveolar compartment. Am J Physiol1996; 270: L736—L744.
37.
Strohmeier GR, Walsh JH, Klings ES et al. Lipopolysaccharide binding protein potentiates airway reactivity in a murine model of allergic asthma. J Immunol2001; 166: 2063—2070.
38.
Piacentini GL, Bodini A., Peroni DG et al. Reduction in exhaled nitric oxide immediately after metacholine challenge in asthmatic children. Thorax2002; 57: 771—773.
