Repression of CC16 by cigarette smoke (CS) exposure

Abstract

Club (Clara) Cell Secretory Protein (CCSP, or CC16) is produced mainly by non-ciliated airway epithelial cells including bronchiolar club cells and the change of its expression has been shown to associate with the progress and severity of Chronic Obstructive Pulmonary Disease (COPD). In an animal model, the lack of CC16 renders the animal susceptible to the tumorigenic effect of a major CS carcinogen. A recent population-based Tucson Epidemiological Study of Airway Obstructive Diseases (TESAOD) has indicated that the low serum CC16 concentration is closely linked with the smoke-related mortality, particularly that driven by the lung cancer. However, the study of CC16 expression in well-defined smoke exposure models has been lacking, and there is no experimental support for the potential causal link between CC16 and CS-induced pathophysiological changes in the lung. In the present study, we have found that airway CC16 expression was significantly repressed in COPD patients, in monkey CS exposure model, and in CS-induced mouse model of COPD. Additionally, the lack of CC16 exacerbated airway inflammation and alveolar loss in the mouse model. Therefore, CC16 may play an important protective role in CS-related diseases.

Figure 1. CC16 was downregulated in human COPD.

Tissue sections from 5 normal subjects (A), 4 moderate (B) and 3 severe COPD patients (C) were stained with CC16 antibody (Green) and counter-stained with DAPI for nuclei (Blue). For each slide, the images were taken and quantified from at least 5 different regions of each tissue slides (D). (&: p<0.05).

Figure 2. CC16 was repressed in non-human primates exposed to CS.

Rhesus monkey was exposed to CS as described in Material and Method Section. Tissue sections from A) 3 filtered air (FA)- and B) 6 CS-exposed monkeys were stained with CC16 antibody (Green) and counter-stained with DAPI for nuclei (Blue). For each slide, the images were taken and quantified from at least 5 different regions of each tissue slides (C). (&: p<0.05).

Figure 3. CC16 was downregulated in WT mouse when exposed to CS.

Both WT and CC16 KO mice were exposed to CS. CC16 staining (Green) was performed on lung tissues from WT or KO mice exposed to FA or CS.

Figure 4. Enlargement of Alveolar Space (represented by the mean linear intercept, μm)

*: p<0.05, CS vs. FA. $: p< 0.05, KO+CS vs. WT +CS.