Allergic asthma is a complex chronic inflammatory airway disease in which many immune cells such as mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells and cellular elements play different roles. The Th2 hypothesis for asthma was first proposed by Mosmann in 1989 . He identified two different subtypes of T helper cells in mice namely Th1 and Th2  that produced a variety of cytokines and were reciprocally inhibitory. Th1 cells produce IFN-γ, IL-2 and IL-12, which activate mechanisms important for defense against viruses and bacteria . Th2 cells produce cytokines (IL-4, IL-5, IL-6, IL-9, and IL-13), which are important in allergic inflammation and defense against parasites. The Th2 hypothesis of asthma suggests that an imbalance in Th1/Th2 immunity plays an important role in the pathogenesis of allergic asthma . Inhaled corticosteroids (ICS) are recommended as a first-line treatment for asthma by international guidelines. However, a study conducted by Ma et al. showed that the early application of glucocorticoids was a risk factor for human enterovirus 71(HEV71) infection . Recent studies have also shown that topical glucocorticoids compromise the barrier function of normal skin, especially during atopic dermatitis [17, 18]. Jamieson et al. showed that a sustained increase in serum glucocorticoid levels in mice with influenza suppressed the systemic antibacterial innate immune response . In the present study, inhaled budesonide decreased the extent of inflammation and cellular infiltration in the airways and the level of IL-4 in OVA-challenged mice. Because allergic airway tissues contain cytokines that promote bacterial infection and colonization in asthma and other lung diseases, Th2 cytokines may be relevant to infection in asthma patients . However, OVA-challenged mice treated with inhaled budesonide and exposed to P. aeruginosa were characterized by the extensive infiltration of numerous inflammatory cells around bronchioles, alveoli, and blood vessels. This indicated that inhaled budesonide increased lung inflammation, reduced the clearance of P. aeruginosa, and increased the severity of pulmonary infection in OVA-challenged mice exposed to P. aeruginosa. Infection with P. aeruginosa was associated with increased levels of IL-4 in OVA-challenged mice treated with budesonide. Thus, our study indicated that inhaled budesonide increased lung infection in mice with allergic inflammation exposed to P. aeruginosa, independent of levels of IL-4.
Airway epithelial cells secrete numerous antimicrobial molecules that are part of the host’s first line of defense against microbial invasion. Antimicrobial products secreted constitutively and/or inducibly by epithelial cells include lysozymes, lactoferrin, defensins, collectins, pentraxins, cathelicidin, secretory leukocyte protease inhibitor (SLPI), and serum amyloid A (SAA) . Defensins and cathelicidins are primary AMP factors expressed in the lung and secreted by airway epithelial cells, macrophages, neutrophils, and other classical host defense cells. Another recent study demonstrated that IL-4 and IL-13 have an inhibitory effect on antimicrobial activity of the airway epithelium, as airway epithelial cells were unable to kill bacteria when incubated with these cytokines . Mice with allergic airway inflammation showed significantly more viable bacteria in their lungs after infection. Th2-based inflammation was also found to suppress host defense and reduce AMP expression in the skin [7, 22]. Thus, the adaptive immune system modulates the functions of the innate immune system and allergic inflammatory diseases inhibit antimicrobial host defense.
Inhaled corticosteroids are currently considered the most effective means of reducing airway inflammation, symptoms, and morbidity in patients with asthma. Glucocorticoids were shown to affect the synthesis of antimicrobial peptides in amphibian skin , inhibit NF-κB signaling and induce immunosuppression in mammalian cell cultures . Mitchell et al. showed that bronchial biopsy specimens from dexamethasone-treated calves had significantly lower levels of tracheal antimicrobial peptide mRNA expression than untreated controls. Thus, corticosteroids may impair innate pulmonary defenses through the regulation of epithelial antimicrobial peptide expression . Tomita et al. demonstrated that glucocorticoids inhibited the release of β-defensin-2 stimulated by lipopolysaccharide in an airway cell line . Aberg et al. showed that psychological stress and systemic and topical glucocorticoid therapy down-regulated epidermal antimicrobial peptide expression and increased the risk of extracutaneous infection in mice . Roca-Ferrer et al. demonstrated that glucocorticoid treatment could cause a modest (30–40%) inhibition of spontaneous lactoferrin secretion in cultured nasal and bronchial mucosa . However, whether ICS can affect anti-microbial host defense among asthma patients remains unclear. In the present study, inhaled budesonide inhibited the production of CRAMP in the antibacterial immune response of OVA-challenged mice. AMP expression was localized to epithelial cells in normal lung tissues and expressed in epithelial cells and inflammatory cells in lung tissues of allergen-challenged mice. Thus, inhaled budesonide suppressed pulmonary antibacterial host defense in an asthmatic mouse model and was dependent on AMPs.
Inhaled corticosteroids induced candidiasis in clinical trials, but the association between the use of inhaled corticosteroids in patients with asthma and the risk of development of community-acquired pneumonia (CAP) remains controversial.
P. aeruginosa is the leading pathogenic cause of detrimental chronic lung infections, and is a major determinant of morbidity and mortality. Asthma patients with bronchiectasis are not rare, and their conditions are often exacerbated by P. aeruginosa status. Airway epithelial cells play a critical role in the orchestration of innate defense and inflammatory responses. P. aeruginosa can adhere to airway epithelial cells and internalization has been observed . In the present study, budesonide increased the number of internalized P. aeruginosa organisms in MLE-12 cells in vitro. The effect of budesonide on bacteria CFU in MLE-12 cells was dose-dependent. High doses of budesonide significantly decreased CRAMP, which was associated with antibacterial host defense.