Smoking Attenuates Efficacy of Penehyclidine Hydrochloride in Acute Respiratory Distress Syndrome Induced by Lipopolysaccharide in Rats

Abstract

BACKGROUND Penehyclidine hydrochloride is a novel drug for acute respiratory distress syndrome. The aim of the study was to reveal the impact of smoking on the efficacy of the drug in rats with acute respiratory distress syndrome. MATERIAL AND METHODS A 132 Sprague-Dawley rats were used in this study; 72 rats were used in the smoking models. Penehyclidine hydrochloride (3 mg/kg) was injected to induce acute respiratory distress syndrome. Rats were divided into the smoking group and the non-smoking group; these 2 groups were subdivided according to different treatments. The arterial blood gas analysis (PaO₂/FiO₂) and extent of pneumonedema (wet-to-dry weight ratio) was analyzed to evaluate disease severity. Expressions of mitogen-activated protein kinases (p-p38MAPK, p38MAPK, p-ERK, ERK, p-JNK, and JNK) in lung tissue were measured using western blot assay. RESULTS Penehyclidine hydrochloride improved the pneumonedema (wet-to-dry weight ratio) and hyoxemia (PaO₂/FiO₂) of the disease in non-smoking group (P<0.001, P<0.001 respectively), but not in smoking group (P=0.244, P=0.424 respectively). The drug inhibited the expressions of phospho-p38MAPK and phospho-ERK in non-smoking group (P<0.001, P<0.001 respectively), but not in smoking group (P=0.350, P=0.507 respectively). In the smoking group, blocking the phospho-p38MAPK or phospho-ERK signal pathway by their inhibitors showed a better therapeutic effect on the pneumonedema and hyoxemia compared with the use of penehyclidine hydrochloride (phospho-p38MAPK: P=0.004, P=0.010 respectively; phospho-ERK: P=0.022, P=0.004 respectively). CONCLUSIONS The study confirmed the protective effect of penehyclidine hydrochloride in acute respiratory distress syndrome, mainly in the non-smoking group, which might be explained by the fact that phospho-p38MAPK and phospho-ERK signal pathways were difficult to inhibit by the drug in the smoking group.

Figure 1

Flow chart in the study. PHC – penehyclidine hydrochloride; ARDS – acute respiratory distress syndrome.

Figure 2

Characteristics of the lung tissue specimens stained by hematoxylin-eosin in the rats (original magnification 100×). Pulmonary edema is indicated by the arrowheads. PHC – penehyclidine hydrochloride; ARDS – acute respiratory distress syndrome.

Figure 3

Characteristics of the pathological and physiological indicators in the arterial blood and lung tissue specimens. (A–C) BALF levels of TNF-α, IL-6, and ALB between the control rats and the PHC rats both in the smoking group and the non-smoking group. (D, E) The W/D ratios and MPO activities of control rats, PHC rats, and ARDS rats in the smoking group and the non-smoking group. (F) The PaO₂/FiO₂ ratios of control rats, PHC rats, and ARDS rats in the smoking group and the non-smoking group. The detailed results were shown in Table 1. ^# Compared with the PHC rats, P<0.05; * compared with the ARDS rats, P<0.05. PHC – penehyclidine hydrochloride; ARDS – acute respiratory distress syndrome; TNF-α – tumor necrosis factor-α; IL-6 – interleukin-6; ALB – albumin; W/D – wet-to-dry weight; MPO – myeloperoxidase.

Figure 4

Kaplan-Meier survival analyses in the rats. (A) The survival rate was equivalent between the treatment rats and the acute respiratory distress syndrome (ARDS) rats in the smoking group (P=0.383). (B) The treatment rats showed significantly higher survival rate compared with the ARDS rats in the non-smoking group (P=0.024).

Figure 5

(A–D) Expression levels of mitogen-activated protein kinases in the lung tissue specimens. ^# Compared with the control rats, P<0.05; * compared with the ARDS rats, P<0.05. The detailed results were shown in Table 2. PHC – penehyclidine hydrochloride; ARDS – acute respiratory distress syndrome.

Figure 6

(A–D) Potential roles of M-receptor and mitogen-activated protein kinase signal pathways in the rats. ALB – albumin; W/D – wet-to-dry weight; MPO – myeloperoxidase. ^# Compared with the treatment rats in the non-smoking group, P<0.05; * compared with the treatment rats in the smoking group, P<0.05. The detailed results were shown in Table 3.