Therapy With Macrolides in Patients With Cystic Fibrosis

Allyson S. Gaylor, Pharm.D., Joan C. Reilly, Pharm.D.

Pharmacotherapy. 2002;22(2) 

In This Article

Pathophysiology of Inflammation

Inflammation is a tissue response to injury or infection with the function of bringing cells of the immune system to the site of damage (Figure 2). Neutrophils are generally the first cells to arrive at the site, and the characteristic feature of airway inflammation in cystic fibrosis is massive infiltration of neutrophils.[45] Neutrophil accumulation is induced by chemotactic mediators such as interleukin (IL)-1, tumor necrosis factor (TNF)-a, IL-8, leukotriene (LT)B4, and endotoxin.[39] Recruitment of neutrophils is a crucial host response against bacterial and fungal invasion, but when present in great excess leads to more harm than good.[45,46] Neutrophils release large amounts of cytokines, oxidants, protease, and elastase, which perpetuate the inflammatory cycle and damage tissue in the lungs.

Inflammatory pathophysiology in cystic fibrosis. IL-8 = interleukin-8; LTB4 = leukotriene B4; IL-1 = interleukin-1; TNF-a = tumor necrosis factor a.

One bactericidal mechanism of neutrophils is production of reactive oxygen metabolites during an oxidative burst. Excessive oxidant generation is involved in cell and tissue damage associated with severe inflammatory reactions.[46] Excessive elastase production contributes to lung damage by digesting elastin and other structural proteins in the airway wall, eventually leading to bronchiectasis. Elastase also impairs phagocytosis leading to persistent infection, increases mucus secretions, and contributes to the inflammatory cycle by generating chemo-attractants IL-8 and LTB4.[45] The inflammatory cycle is balanced by the presence of antiproteases and the antiinflammatory cytokine IL-10, both of which are decreased in patients with cystic fibrosis.[47,48] When the antiprotease capacity is exceeded, tissue damage can become extensive since protease enzyme activity is unhindered. This occurs in cystic fibrosis due to the immense neutrophil influx.

Many cytokines are involved in the inflammatory process (Table 2). Several, including IL-8, IL-1, TNF-a, and LTB4, are elevated in the sputum of patients with DPB and cystic fibrosis.[40,46,49] Interleukin-8, produced by monocytes and macrophages, is the major neutrophil chemotactic factor in the lungs. Tumor necrosis factor-a, released by macrophages and other cells, has cytotoxic activity and promotes transendothelial migration. It is also a potent stimulus for the induction of IL-8. Interleukin-1 has many similar effects to TNF-a and also acts to produce prostaglandins and promote tissue remodeling. Both TNF-a and IL-1 can stimulate oxygen radical release and expression of adhesion molecules, thereby leading to amplified local inflammatory damage. Interleukin-1 and TNF-a initiate and maintain the acute phase of the inflammatory response, and IL-8 and LTB4 recruit more neutrophils to the airways. The constant cycle of inflammation begins at an early age and continues throughout life, eventually leading to lung tissue damage and bronchiectasis, which are accompanied by a progressive decline in pulmonary function.


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