The role of neutrophils in LPS-induced changes in pulmonary function in conscious rats.
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.
Spond
J
J
Schering Plough Research Institute, Allergy and Immunology, 2015 Galloping Hill Rd, K-15-1600, Kenilworth, NJ 07033, USA.
Billah
M M
MM
Chapman
R W
RW
Egan
R W
RW
Hey
J A
JA
House
A
A
Kreutner
W
W
Minnicozzi
M
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015656:Respiratory Mechanics / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D008070:Lipopolysaccharides