**2. Mechanisms of Asthmatic Airway Inflammation and Role of HO-1**

Asthma is a heterogeneous disease characterized by chronic airway inflammation and bronchial hyperresponsiveness. As a protective protein, many studies prove that HO-1 expression is upregulated both in asthma patients [13–15] and animal models of asthma [6,16–18]. The pathophysiological significance of this phenomenon is to avoid further deterioration of inflammation since inhibition of endogenous HO-1 further aggravates the inflammation [9,10]. Furthermore, upregulation of HO-1 or exogenous administration of CO and bilirubin which is produced by its degradation of heme has significant protective effects on allergic airway inflammation. These factors can inhibit plasma exudation to the trachea, main bronchi, and segmental bronchi; reduce infiltration of inflammatory cells (such as EOS, neutrophils, lymphocytes, and macrophages) around the airway and in bronchoalveolar lavage fluid (BALF); alleviate airway reactivity and mucus secretion [19–22]; decrease the proportion of antigen-specific Th2 cells [6] and Th17 cells [12,23] in mediastinal lymph nodes and the spleen; and further inhibit allergic airway inflammation. These findings suggest that HO-1 has a protective effect in various types of asthmatic airway inflammation.

The pathogenesis of asthma is complex, and immune imbalance is the most important mechanism of asthma. Th2 immune response-dominant asthma (the most common phenotype) involves EOS inflammation, while Th17 immune response-dominant asthma (the primary refractory phenotype) involves neutrophil inflammation. Regardless of type, this immune disorder proceeds through initiation, Th cell-directed differentiation, amplification, and effective stages. The initiation stage is particularly important because it determines the direction of the immune response. During the initiation of immune responses, antigen-presenting cells (APCs) and T cells interact with each other via the T cell receptor (TCR)–major histocompatibility complex (MHC) peptide complex and costimulatory molecules on the cell surface. In the context of specific cytokine environments, these interactions direct naïve T cell differentiation into antigen-specific Th cells (Th1, Th2, and Th17). Thus, the state and microenvironment of APCs determine the type of T cell immune response. During the effective stage, cytokines secreted by Th2 cells infiltrate around the airway along with EOS, MCs, and BAs, resulting in further release of inflammatory mediators that promote EOS infiltration-domain allergic airway inflammation. Th17 cells, mainly chemotax neutrophils, cause neutrophil-dominant airway inflammation [24–27]. Thus, various immune cells participate in the formation of chronic airway inflammation during asthma onset. HO-1 has important regulatory effects on multiple types of immune cells involved in airway inflammation [6,12,19–23].

#### **3. HO-1 Inhibits Inflammation during the Initial Stage**
