Inhalation of LPS induces inflammatory airway responses mimicking characteristics of chronic obstructive pulmonary disease Magnus Korsgren 1 , Margareta Linden 2 , Neil Entwistle 3 , Jason Cook 3 , Per Wollmer 4 , Morgan Andersson 5 , Bengt Larsson 1,2 and Lennart Greiff 5 1 Department of Clinical Pharmacology, Lund University Hospital, Lund, 2 AstraZeneca R&D Lund, Lund, Sweden, 3 AstraZeneca R&D Charnwood, Loughborough, UK, 4 Department of Clinical Physiology, Lund University Hospital, Malmo¨, and 5 Department of Otorhinolaryngology, Lund University Hospital, Lund, Sweden Correspondence Lennart Greiff, Department of Otorhinolaryngology, Lund University Hospital, SE-221 85 Lund, Sweden E-mail: lennart.greiff@live.se Accepted for publication Received 5 March 2011; accepted 6 September 2011 Key words airway inflammation; C-reactive protein; endotoxin; neutrophil elastase; neutrophils; tumour necrosis factor-a Summary Aim: Inhalation of lipopolysaccharide (LPS) produces both systemic and pulmonary inflammatory responses. The aim of this study was to further characterize the response to LPS in order to develop a human model suitable for early testing of drug candidates developed for the treatment for chronic obstructive pulmonary disease (COPD). Materials: Blood and induced sputum were obtained 4, 24 and 48 h following inhalation of saline and LPS (5 and 50 lg). Blood was analysed for C-reactive protein (CRP), a 1 -antitrypsin and neutrophils ⁄ leucocytes, and sputum was analysed for biomarkers of neutrophil inflammation and remodelling activities, i.e. neutrophil elastase (NE) protein ⁄ activity and a 1 -antitrypsin. Levels of tumour necrosis factor-a (TNFa) were measured in both blood and sputum. Urine was collected 0–24 and 24–48 h postchallenge, and desmosine, a biomarker of elastin degradation, was measured. Results: Lipopolysaccharide inhalation induced dose-dependent flu-like symptoms and increases in plasma CRP and a 1 -antitrypsin as well as increases in blood neutrophil ⁄ leucocyte numbers. Furthermore, LPS produced increases in sputum TNFa and sputum NE activity. Urine levels of desmosine were unaffected by the LPS challenge. All subjects recovered 48 h postchallenge, and indices of inflammatory activity were significantly lower at this observation point cf 24 h postchallenge. Conclusion: Inhalation of LPS in healthy volunteers can be used as a safe and stable model of neutrophil inflammation. Blood ⁄ plasma and sputum indices can be employed to monitor the response to LPS. We suggest that this model may be used for initial human studies of novel COPD-active drugs. Introduction Chronic obstructive pulmonary disease (COPD) afflicts about 5% of the western population. Despite its severity, the condition is poorly treated, reflecting a lack of efficient COPD-active drugs. Human models suitable for early and fast evaluation of novel drug candidates with a potential to speed up drug development in this field are warranted. Lipopolysaccharide (LPS), or endotoxin, is a constituent of the outer cell membrane of gram-negative bacteria. Oral inhalation of LPS in man evokes airway inflammation charac- terized by increased neutrophil activity (Michel et al., 1992, 1995, 1997; Sandstro ¨m et al., 1992; Nightingale et al., 1998a,b; Tho ¨rn & Rylander, 1998). Although there are systemic features of the response to LPS, the inflammation appears to be fully transient and repeatable. Hence, LPS challenges may have a utility for studies of the pharmacology of neutrophilic airway inflammation. In turn, such studies may be relevant to conditions characterized by neutrophilic inflammation, includ- ing COPD (Lacoste et al., 1993; Keatings & Barnes, 1997; Rutgers et al., 2000). Macrophages are regarded as one of the major players in the pathophysiology of COPD, including a role in airway remod- elling activities (McLaughlin & Tueller, 1971; Barnes, 2004). LPS stimulates macrophages, leading to the production of many pro-inflammatory factors, including tumour necrosis factor-a Clin Physiol Funct Imaging (2012) 32, pp71–79 doi: 10.1111/j.1475-097X.2011.01058.x Ó 2011 The Authors Clinical Physiology and Functional Imaging Ó 2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine 32, 1, 71–79 71