Hyperosmolar Solution Effects in Guinea Pig Airways. IV. Lipopolysaccharide-Induced Alterations in Airway Reactivity and Epithelial Bioelectric Responses to Methacholine and Hyperosmolarity

Abstract

We investigated the in vivo and in vitro effects of lipopolysaccharide (LPS) treatment (4 mg/kg i.p.) on guinea pig airway smooth muscle reactivity and epithelial bioelectric responses to methacholine (MCh) and hyperosmolarity. Hyperosmolar challenge of the epithelium releases epithelium-derived relaxing factor (EpDRF). Using a two-chamber, whole body plethysmograph 18 h post-treatment, animals treated with LPS were hyporeactive to inhaled MCh aerosol. This could involve an increase in the release and/or actions of EpDRF, because LPS treatment enhanced EpDRF-induced smooth muscle relaxation in vitro in the isolated perfused trachea apparatus. In isolated perfused tracheas the basal transepithelial potential difference (V t ) was increased after LPS treatment. The increase in V t was inhibited by amiloride and indomethacin. Concentration-response curves for changes in V t in response to serosally and mucosally applied MCh were biphasic (hyperpolarization, Ͻ3 ϫ 10 Ϫ7 M; depolarization, Ͼ3 ϫ 10 Ϫ7 M); MCh was more potent when applied serosally. The hyperpolarization response to MCh, but not the depolarization response, was potentiated after LPS treatment. In both treatment groups, mucosally applied hyperosmolar solution (using added NaCl) depolarized the epithelium; this response was greater in tracheas from LPStreated animals. The results of this study indicate that airway hyporeactivity in vivo after LPS treatment is accompanied by an increase in the release and/or actions of EpDRF in vitro. These changes may involve LPS-induced bioelectric alterations in the epithelium.Asthma is a chronic disease that is characterized by reversible airway obstruction, airway inflammation, and airway hyperresponsiveness. Lipopolysaccharide (LPS) or endotoxin, the major component of the outer membrane of gram negative bacteria, poses problems for asthmatic patients. For example, inhaled endotoxin causes a slight decrease in the forced expiratory volume in 1 s and an increase in histamine responsiveness in asthmatic patients, but not in normal subjects (Michel et al., 1989(Michel et al., , 1996. Several reports have demonstrated that LPS administration leads to the development of airway hyperreactivity and inflammation in mice (Held and Uhlig, 2000), rats (Pauwels et al., 1990), and guinea pigs (Toward and Broadley, 2000).Airway reactivity is under the control of numerous physiological mechanisms, including epithelial-derived excitatory and inhibitory substances (Fedan et al., 1988;Goldie and Hay, 1997;Folkerts and Nijkamp, 1998). One such inhibitory substance that has been shown to modulate airway reactivity is the non-nitric oxide nonprostanoid epithelium-derived relaxing factor (EpDRF), which is released in response to hyThis work was supported, in part, by National Institutes of Health Grant 5-T32-GM07039 (to R.A.J.). Mention of brand name does not constitute product endorsement. This article is the fourth one of a series of four companion articles that report the effects of hyperosmolar solutions in guinea pig airways ...

Hyperosmolar Solution Effects in Guinea Pig Airways. I. Mechanical Responses to Relative Changes in Osmolarity

“…Mention of brand name does not constitute product endorsement. This article is the first one of a series of four companion articles that report the effects of hyperosmolar solutions in guinea pig airways Johnston et al, 2003;Wu et al, 2003).…”

“…In guinea pig tracheal epithelium, EpDRF is released by hyperosmolar challenge of the apical or basolateral membranes (Dortch-Carnes et al, 1999;Fedan et al, 1999). EpDRF is neither nitric oxide nor a prostanoid (Munakata et al, 1990;Spina and Page, 1991;Fedan et al, 1999;Johnston et al, 2003) but has attributes that resemble, in part, but not completely, carbon monoxide . Most cells placed in a hyperosmolar environment shrink initially and then undergo a regulatory volume increase, the latter involving early electrolyte accumulation and delayed uptake of compatible osmolytes, e.g., betaine, myo-inositol, sorbitol, and taurine (Lang et al, 1998).…”

Hyperosmolar Solution Effects in Guinea Pig Airways. II. Epithelial Bioelectric Responses to Relative Changes in Osmolarity

“…EpDRF is released in association with transepithelial depolarization (Dortch-Carnes et al, 1999) and is associated with Na ϩ and Cl Ϫ transport, as judged by the inhibitory effects of Na ϩ and Cl Ϫ channel blockers . EpDRF is neither nitric oxide nor a prostanoid (Munakata et al, 1990;Spina and Page, 1991;Fedan et al, 1999Fedan et al, , 2003aJohnston et al, 2003).…”

“…Mention of brand name does not constitute product endorsement. This article is the second one of a series of four companion articles that report the effects of hyperosmolar solutions in guinea pig airways (Fedan et al, 2003a,b;Johnston et al, 2003).…”

Hyperosmolarity-Induced Dilation and Epithelial Bioelectric Responses of Guinea Pig Trachea in Vitro: Role of Kinase Signaling

“…EpDRF has not been isolated. Dilation responses of the perfused trachea triggered by challenge of the epithelium with hyperosmolar solution are not mediated by nitric oxide or prostanoids (Munakata et al, 1990;Johnston et al, 2004). The responses are partially inhibited by hemoglobin and zinc II protoporphyrin(IX) (Fedan et al, 2004b), which suggests that carbon monoxide contributes to the activity known as EpDRF.…”