The role of neutrophils in LPS-induced changes in pulmonary function in conscious rats

• Published in: Pulmonary pharmacology & therapeutics Vol. 17; no. 3; pp. 133 - 140
• Main Authors: Spond, J., Billah, M.M., Chapman, R.W., Egan, R.W., Hey, J.A., House, A., Kreutner, W., Minnicozzi, M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2004
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Breathing frequency; Bronchoconstriction; Bronchodilator Agents - pharmacology; Lipopolysaccharides; Lung - pathology; Lung - physiopathology; Male; Neutrophils - physiology; Penh; Pneumonia - chemically induced; Pneumonia - pathology; Pneumonia - physiopathology; Pulmonary inflammation; Rats; Rats, Sprague-Dawley; Respiratory Mechanics - drug effects; Tidal volume; Pulmonary inflammation; Bronchoconstriction; Penh; Breathing frequency; Tidal volume
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1016/j.pupt.2004.01.003

We have previously reported on a model of lipopolysaccharide (LPS)-induced pulmonary inflammation in rats, where LPS-challenged animals develop a significant pulmonary neutrophilia and mucus hypersecretion. In the current studies, we utilized whole body plethysmography and computer assisted data acquisition to examine changes in pulmonary parameters, e.g. frequency ( f), tidal volume and Penh as a measure of bronchoconstriction, due to LPS-challenge in conscious rats. Compared to saline challenge, LPS-challenged rats displayed a significant increase in ( f), which began within 30 min, peaked by 2 h and remained elevated up to 24 h. Mirroring this increase in ( f) was a decrease in the observed tidal volume of LPS-challenged rats. Additionally, compared to saline challenge, LPS-challenge provoked a significant and spontaneous bronchoconstriction, as measured by Penh, 2 h after challenge. In order to further understand these observed LPS-induced pulmonary changes, we utilized two classes of pulmonary obstructive disease standards, namely, bronchodilators and anti-inflammatory agents, and examined their ability to affect the spontaneous bronchoconstriction and the increase in ( f) seen at two discrete time points, i.e. 2 and 24 h after LPS-challenge. While ineffective on either the 2 h increase in ( f) or the LPS-induced inflammation, animals pretreated with salbutamol (10 mg/kg, p.o.) were protected from the increase in ( f) seen at the 24 h time point after LPS-challenge. In contrast, when animals were pretreated with theophylline (10 mg/kg, p.o.) no effect on the LPS-induced pulmonary inflammation or increase in ( f) was noted. Meanwhile, in animals pretreated with either betamethasone (3 mg/kg, p.o.) or SB207499 (10 mg/kg, p.o.), a PDE4 inhibitor, doses previously shown to block the LPS-induced neutrophilic inflammation, the persistent increase in ( f) seen at 24 h was attenuated, but neither compound was able to attenuate either the increase in ( f) or the spontaneous bronchoconstriction seen at 2 h. In summary, the intra-tracheal LPS-challenge of rats results in pulmonary inflammation and dysfunction, which is similar to that seen in COPD patients. We conclude that the early increase in ( f) and bronchoconstriction are not dependent upon airway inflammation, but airway inflammation most likely contributes to the persistent increase in ( f) seen at 24 h.