Abnormal proteolytic activity is associated with many diseases. In pancreatitis, leakage of proteases and their premature activation in the pancreas results in the self-digestion of the pancreas. People with diabetes mellitus may have increased lysosomal activity and the degradation of some proteins can increase significantly. Chronic inflammatory diseases such as rheumatoid arthritis may involve the release of lysosomal enzymes into extracellular space that break down surrounding tissues. Abnormal proteolysis may result in many age-related neurological diseases such as Alzheimer's due to generation and ineffective removal of peptides that aggregate in cells.
Proteases may be regulated by antiproteases or protease inhibitors, and imbalance between proteases and antiproteases can result in diseases, for example, in the destruction of lung tissues in emphysema brought on by smoking tobacco. Smoking is thought to increase the neutrophils and macrophages in the lung which release excessive amount of proteolytic enzymes such as elastase, such that they can no longer be inhibited by serpins such as α-antitrypsin, thereby resulting in the breaking down of connective tissues in the lung. Other proteases and their inhibitors may also be involved in this disease, for example matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).
Other diseases linked to aberrant proteolysis include muscular dystrophy, degenerative skin disorders, respiratory and gastrointestinal diseases, and malignancy.