A well-recognized example for severely susceptibility is the severe deficiency of α-1 antitrypsin, which is the major inhibitor of neutrophil elastase. The severe α-1 antitrypsin deficiency is present in only 1–2% of individuals with COPD . As neutrophil elastase functions to degrade macrophage elastase inhibitor of metalloproteinase-1, the severe α-1 antitrypsin deficiency significantly increases the tissue destruction activity of macrophage elastase . Therefore, the overall effect of the severe α-1 antitrypsin deficiency is to significantly enhance the M1-induced TD generation , corresponding to the case where k13 adopts a relatively large value for a severely susceptible smoker (Fig 9).