Protective effects of tiotropium alone or combined with budesonide against cadmium inhalation induced acute neutrophilic pulmonary inflammation in rats

Abstract

As a potent bronchodilator, the anti-inflammatory effects of tiotropium and its interaction with budesonide against cadmium-induced acute pulmonary inflammation were investigated. Compared to values obtained in rats exposed to cadmium, cytological analysis indicated a significant decrease of total cell and neutrophil counts and protein concentration in bronchoalveolar lavage fluid (BALF) in rats pretreated with tiotropium (70μg/15ml or 350μg/15ml). Zymographic tests showed a decrease of MMP-2 activity in BALF in rats pretreated only with high concentration of tiotropium. Histological examination revealed a significant decrease of the severity and extent of inflammatory lung injuries in rats pretreated with both tested concentrations of tiotropium. Though tiotropium (70μg/15ml) or budesonide (250μg/15ml) could not reduce cadmium-induced bronchial hyper-responsiveness, their combination significantly decreased bronchial contractile response to methacholine. These two drugs separately decreased the neutrophil number and protein concentration in BALF but no significant interaction was observed when both drugs were combined. Although no inhibitory effects on MMP-2 and MMP-9 was observed in rats pretreated with budesonide alone, the combination with the ineffective dose of tiotropium induced a significant reduction on these parameters. The inhibitory effect of tiotropium on lung injuries was not influenced by budesonide which alone induced a limited action on the severity and extent of inflammatory sites. Our findings show that tiotropium exerts anti-inflammatory effects on cadmium-induced acute neutrophilic pulmonary inflammation. The combination of tiotropium with budesonide inhibits cadmium-induced inflammatory injuries with a synergistic interaction on MMP-2 and MMP-9 activity and airway hyper-responsiveness.

Muscarinic receptor antagonists and airway inflammation: A systematic review on pharmacological models

“…Of the 268 potentially relevant records identified in the initial search, 43 studies were deemed eligible for a qualitative analysis. Overall, this systematic review included data obtained from 28 in vivo studies performed on research animals [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], 11 in vitro studies [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ], 3 studies conducted both in vitro and in vivo [ 69 , 70 , 71 ], and 1 clinical study performed in patients with COPD and then conducted ex vivo [ 72 ] ( Table 2 ).…”

“…In Sprague–Dawley rats, a single or repeated exposure for 5 weeks to CdCl 2 0.1% in saline by inhalation significantly (P < 0.05) increased the number of total inflammatory cells, neutrophils, total protein concentration, and the activity of MMP-2 and MMP-9 in the BALf [ 48 , 49 , 51 ]. CdCl 2 did not induce a significant variation in IL-1β [ 48 , 49 ] and TNF-α release [ 48 , 49 , 51 ], although Zhao et al. [ 51 ] reported an increase in IL-1β BALf concentration after a single challenge.…”

The Impact of Muscarinic Receptor Antagonists on Airway Inflammation: A Systematic Review

“… Lung:≈ 34 * / Lung:≈ 34 * / BALf:≈ 34 * . Lung:≈ 34 * / / / / RB Lung: ↓ 40%IRB, 50%IRB, 60%ERB, and 40%/60%CRB 45 / / Lung: ↓ 40%IRB, 50%IRB, 60%ERB, and 40%/60%CRB 45 / / / / / / / / / / / / / / / CdCl 2 BALf:≈ 47 / / / / / / / / / / / / / BALf:≈ 47 BALf:↓ 47 BALf:≈ 47 / / LPS / / / BALf:↓ 30 / / / / …”

“…TIO also suppressed the CdCl 2 -induced infiltration of neutrophils and macrophages in the alveoli, peri-bronchial regions and parenchyma, thus reducing the inflammatory scores associated with the severity and extent of histological injuries. 47 …”

Tiotropium Bromide Has a More Potent Effect Than Corticosteroid in the Acute Neutrophilic Asthma Mouse Model

“…The experimental drugs used TIO and dexamethasone (DEX). TIO (25 μg/mL) was administered by inhalation for 3 minutes per mouse in the inhalation chamber [ 16 ]. This was done on days 21, 22, and 23 ( Figure 1 ).…”