Th2-Biased Immune Responses Are Important in a Murine Model of Chronic Hypersensitivity Pneumonitis

Abstract

Background: Chronic hypersensitivity pneumonitis (HP) can lead to irreversible pulmonary fibrosis. A good animal model is essential to elucidate the mechanisms of this disease. We previously reported that a Th2 predominance may play an important role in the fibrogenesis in chronic HP patients. A study was undertaken to evaluate whether Th2-biased immune responses were crucial during the processes of lung fibrosis in a murine model of chronic HP. Methods: Instillation of pigeon dropping extracts (PDE) was conducted 3 days a week for 6 or 12 weeks in C57BL/6, BALB/c and A/J mice to establish models of chronic HP. We evaluated the histopathological features, immunohistochemistry, collagen content, bronchoalveolar lavage fluid (BALF) profiles and Th1/Th2 cytokines in BALF or lung tissue with RT-PCR and ELISA. Results: Thickening of the alveolar walls and structural alterations were observed only in the A/J mice after 12 weeks of exposure to PDE. The fibrosis scores were significantly increased in 12-week A/J mice compared to those in the other strains. Immunohistochemistry evaluation showed that PDE was engulfed by alveolar macrophages that were incorporated into the alveolar septa of 12-week A/J mice. Interleukin (IL)-4 mRNA increased significantly in 6- and 12-week A/J mice. IL-13 mRNA showed a significant increase in 12-week A/J mice compared with 6-week A/J mice. TGF-β1 mRNA at 12 weeks was significantly increased in A/J mice compared with the other groups. Conclusion: Th2-biased genetic backgrounds may play an important role in fibrosing processes in the present chronic HP model.

Associations of Pulmonary Fibrosis with Peripheral Blood Th1/Th2 Cell Imbalance and EBF3 Gene Methylation in Uygur Pigeon Breeder’s Lung Patients

“…A study on farmer's lung, another type of HP, revealed that large numbers of lymphocytes and high levels of IL-2 are present in the bronchoalveolar lavage fluid of people exposed to allergens, which might result in lymphocyte accumulation in the lung. Moreover, serum soluble IL-2 receptor was found to be expressed at a high level [17], and PF and Th2 dominance were observed when the disease evolved to the chronic stage; IL-4 was also produced by Th2 cells at a higher level [8]. In our previous study, Th1-associated cytokines were found to be highly expressed in PBL patients.…”

“…According to a clinical study on HP, the expression levels of proinflammatory factors, such as IL-2 and IFN-γ, in bronchoalveolar lavage fluid and TNF-α in serum are markedly increased [4,7]. However, according to an animal study, Th2 cell dominance and PF occur together in chronic stages, and IL-4 is highly expressed [8].…”

Toll-like Receptors 2 and 9 Are Important for Innate Immune Cell Activation and Recruitment in Hypersensitivity Pneumonitis

“…A study which looked at T cell responses in patients with subacute and chronic pigeon breeder's disease, another common type of HP, found an increase in CD4 + and CD8 + T cells expressing IL-4 and a decrease in T cells expressing IFNγ in patients with CHP compared to subacute HP (Barrera et al, 2008). This is in agreement with a mouse model of chronic pigeon breeder's disease in which the authors found that IL-4 / IL-13 expression and a Th2-biased immune response correlated with increased lung fibrosis (Mitaka et al, 2011). Fibrotic diseases are often associated with the expression of Th2-associated cytokines IL-4 and IL-13 (GharaeeKermani et al, 2001;Huaux et al, 2003;Jakubzick et al, 2003;Lee et al, 2001).…”

“…lung fibrosis in the Th2-biased mouse strain A/J (Mitaka et al, 2011). However, in the SR model of HP, IL-17 and a Th17 response is associated with increased fibrosis (Joshi et al, 2009;Simonian et al, 2009).…”

Chronic hypersensitivity pneumonitis caused by Saccharopolyspora rectivirgula is not associated with a switch to a Th2 response

“…These patients were diagnosed with pigeon breeders disease, another type of HP in which the chronic phase is characterized by fibrosis. Similarly, Mitaka et al (28) used the murine model of pigeon breeders disease to demonstrate an association between fibrosis and the Th2 response. However, patients with chronic FLD develop both emphysematous and fibrotic changes in the lung, suggesting that the immunological mechanisms leading to lung damage in HP may differ depending on the environmental antigen triggering the disease (12).…”