**1. Introduction**

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease with the resultant airflow obstruction from the lungs [1,2]. Its symptoms include breathing difficulty, cough, mucus (sputum) production, and wheezing [3,4]. Chronic bronchitis and emphysema are the most common disorders responsible for COPD, being caused by long-term exposure to irritating noxious gases, most often from cigarette smoke (CS) [5]. Chronic bronchitis is inflammation of the lining of the bronchial tubes, and emphysema is a condition in which the alveoli of the lungs are destroyed [6]. In fact, pathological alterations in bronchioles and alveoli lead to a loss of alveolar integrity through activating aberrant inflammatory pathways [5]. Bronchiolar and alveolar epithelial cells can display direct immune and anti-inflammatory responses against lung tissue damage [6,7]. Pulmonary mesenchymal cells such as airway smooth muscle cells and lung fibroblasts can also

respond to inflammatory mediators [6,8]. In COPD, chronic inflammation mainly entails the infiltration of neutrophils, macrophages, CD8+ T lymphocytes, and other inflammatory cells into the small airways [1,6]. Bronchiolar epithelium-derived monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 can be responsible for the chemotactic activity of neutrophils [7,9]. However, the underlying mechanisms for bronchiolar and alveolar inflammation of COPD remain to be solved. Promising mechanisms involved in small airway/alveolar destruction and structural changes may provide major therapeutic targets in COPD [10,11].

Numerous studies have identified diverse therapeutic targets in chronic bronchitis and COPD [11,12]. The major therapeutic option for these diseases is to combat airway inflammation [12,13]. Exposure to CS provokes the recruitment of inflammatory cells into the airways and prompts immune response mechanisms [14]. Thus, the immunomodulatory therapies in airways may effectively alleviate pulmonary diseases [15]. The pathogenesis of emphysema refers to alveolar destruction with airspace enlargement and loss of alveolar integrity by the interaction of apoptosis, oxidative stress, and protease/antiprotease imbalance [14,16]. Oxidative stress is a purported contributor for emphysema through activating pro-inflammatory cytokine transcription [13,17]. The protease/antiprotease imbalance impairs tissues in COPD and emphysema, which is involved in inflammatory processes [17,18]. There are major novel anti-inflammatory agents in COPD targeting lung and systemic inflammation including inhaled corticosteroids and β-adrenergic receptor agonists, phosphodiesterase-4 inhibitors, macrolides, and statins [14,19,20]. These approaches can a ffect more intimately COPD-specific mechanisms of inflammation, mucin production, and tissue destruction and repair [14,16,19]. Currently, such treatments in COPD are not ye<sup>t</sup> justified. Therefore, new therapeutic strategies with natural agents have mostly proven to be safe, and are currently under development for treating airway inflammation [21].

Several studies show potential roles of natural plant extracts and compounds for the treatment of asthma and COPD [22,23]. Anti-inflammatory and antioxidant polyphenols including resveratrol, curcumin, quercetin, sulforaphane, lycopene, mangiferin, and dihydroquercetin suppress experimental pulmonary fibrosis and modulate various biochemical features of COPD [24,25]. A MORGEN study suggests a beneficial e ffect of a high intake of catechins and solid fruits with flavonols and flavones against COPD [26]. Our previous studies revealed that several compounds such astragalin, kaempferol, and oleuropein antagonized airway epithelial apoptosis and fibrosis, Inflammation and airway thickening in ovalbumin (OVA)-challenged mice [27–29]. Additionally, oleuropein rich in olives exhibits favorable e ffects on pulmonary inflammation in CS-challenged mice through blocking recruitment of inflammatory and allergic cells and blunting alveolar destruction [29]. A recent study has reported that dried yeas<sup>t</sup> extracts (YE) may e ffectively inhibit oxidative stress-responsive epithelial eosinophilia and mucus-secreting goblet cell hyperplasia in asthma [30]. However, the beneficial e ffects of YE on smoking-induced inflammation and emphysema in bronchioles and alveoli have not been reported. This study examined whether YE abrogated airway inflammation and apoptotic emphysema in CS- and OVA-challenged mouse models. Pulmonary inflammation and emphysema were also examined in alveolar epithelial cells exposed to cigarette smoke extract (CSE) and lipopolysaccharide (LPS).
