Abstract
We proposed an experimental model to verify the Th17/Treg cytokine imbalance in COPD exacerbation. Forty C57BL/6 mice were exposed to room air or cigarette smoke (CS) (12 ± 1 cigarettes, twice a day, 30 min/exposure and 5 days/week) and received saline (50 µl) or lipopolysaccharide (LPS) (1 mg/kg in 50 µl of saline) intratracheal instillations. We analyzed the mean linear intercept, epithelial thickness and inflammatory profiles of the bronchoalveolar lavage fluid and lungs. We evaluated macrophages, neutrophils, CD4+ and CD8+ T cells, Treg cells, and IL-10+ and IL-17+ cells, as well as STAT-3, STAT-5, phospho-STAT3 and phospho-STAT5 levels using immunohistochemistry and IL-17, IL-6, IL-10, INF-γ, CXCL1 and CXCL2 levels using ELISA. The study showed that CS exposure and LPS challenge increased the numbers of neutrophils, macrophages, and CD4+ and CD8+ T cells. Simultaneous exposure to CS/LPS intensified this response and lung parenchymal damage. The densities of Tregs and IL-17+ cells and levels of IL-17 and IL-6 were increased in both LPS groups, while IL-10 level was only increased in the Control/LPS group. The increased numbers of STAT-3, phospho-STAT3, STAT-5 and phospho-STAT5+ cells corroborated the increased numbers of IL-17+ and Treg cells. These findings point to simultaneous challenge with CS and LPS exacerbated the inflammatory response and induced diffuse structural changes in the alveolar parenchyma characterized by an increase in Th17 cytokine release. Although the Treg cell differentiation was observed, the lack of IL-10 expression and the decrease in the density of IL-10+ cells observed in the CS/LPS group suggest that a failure to release this cytokine plays a pivotal role in the exacerbated inflammatory response in this proposed model.
Highlights
Chronic obstructive pulmonary disease (COPD) is the fourth highest cause of mortality in the world, and it is predicted to become the third cause of death worldwide by 20201,2
The intratracheal instillation of LPS induced a significant increase in the numbers of total cells, macrophages, neutrophils and lymphocytes in the bronchoalveolar lavage fluid (BALF) compared to the Control/SAL and cigarette smoke (CS)/SAL groups (Fig. 2A–D)
An increase in epithelial thickness was observed in the CS/LPS group compared to the Control/SAL group (Fig. 3B,K–N)
Summary
Chronic obstructive pulmonary disease (COPD) is the fourth highest cause of mortality in the world, and it is predicted to become the third cause of death worldwide by 20201,2. Clinical studies have identified a correlation between recurrent respiratory bacterial[11] or viral infections and COPD exacerbation[10,12,13,14], and the pivotal roles of innate and adaptive immune responses in the worsening of this lung disease[15,16]. Regarding the innate immune response, macrophages are part of the first line of lung defense in early events of infections induced by bacterial or viral agents. These cells phagocyte microbes and apoptotic cells to eliminate deleterious agents and are responsible for releasing some pro-inflammatory mediators that promoteing neutrophils migration to the pulmonary site[17]. The effectors immune responses result from the differentiation of naïve CD4+ T cells into Th1, or Th2, or Th17 or regulatory T cells (Treg) depending on the cytokines that signal through the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway[19,20]
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