(Taken directly from the application) The non-steroidal anti-inflammatory drug ibuprofen, at high doses (20-30 mg/kg, b.i.d.), has been shown in a four-year clinical trial to significantly show the progression of lung disease in Cystic Fibrosis patients. Because nonsteroidal anti-inflammatory drugs have previously been reported to inhibit neutrophil (PMN) migration both in vitro and in vivo and because neutrophils are markedly elevated in even the mildest CF patients studied, we have hypothesized that repeated exposure to ibuprofen at high doses inhibits PMN by inhibiting PMN ability to respond to such chemoattractants and other stimuli. We have access to a group of 25 CF patients and 50 normal volunteers who are participating in a study of dose response to ibuprofen and duration of ibuprofen effect, on PMN recruitment to oral mucosa. Additionally, we have access to CF patients who have received high doses of ibuprofen for over 6 months, as well as those who have not received the drug. We will use these subjects to test the above hypotheses.
The specific aims of this proposal are: I) to determine if high doses of ibuprofen lead to a decreased ability of peripheral blood PMNs to synthesize and release pro-inflammatory products in response to physiological stimuli. The products to be studied include LTB4, interleukin (IL)-8, and elastase. The stimuli to be tested include arachidonic acid (to assess LTA synthase/hydrolase activity); A23187 and platelet-activating factor (PAF) to test intracellular signalling pathways, and formyl-methanal-leucyl-phenylalanine (fmlp), to test a physiologically relevant stimulus. II) to determine if high doses of ibuprofen reduce the ability of PMNs to respond functionally to those stimuli. Responses to be measured include chemotaxis and superoxide generation. III) to assess the ibuprofen concentration dependence and duration of effect of ibuprofen on the indicated responses. The results of this study will determine whether and which PMN functions are impaired by regular treatment with high doses of ibuprofen. Such information may lead to discovery of better therapeutic agents in CF with even fewer or less severe potential side effects than ibuprofen.
