Figure 8. Proposed model for the regulation of HAT/HDAC by ProT in emphysema.

(a) Healthy individuals who do not smoke cigarettes maintain the HAT/HDAC balance and thereby sustain normal transcription of NF-κB-dependent genes. (b) Non-smokers who have higher basal ProT levels exhibit reduced association of HDACs with histones in the lung. This leads to enhancing acetylation-mediated chromatin remodelling and thereby upregulating the expression of NF-κB-dependent genes, such as MMP2 and MMP9. Thus, such individuals may develop mild emphysema. (c) In smokers who have normal ProT basal levels, exposure to CS induces ProT expression and nuclear translocation of NF-κB in the lung. This results in reduced HDAC activity and increased acetylation of chromatin and NF-κB, and in turn leads to upregulation of the transcription of NF-κB-dependent genes, such as MMP2 and MMP9. This ultimately causes emphysema. Long-term cigarette smoking may exacerbate this effect and increase the severity of emphysema. (d) In smokers who have higher basal ProT levels, CS exposure further upregulates ProT expression. Excess ProT causes a shift in the HAT/HDAC balance toward HAT. This results in developing severe emphysema. Thus, ProT predisposes individuals to CS-induced emphysema.