Basic Study on Lung Injuries and Neutrophils-Isolation and Purification of Alveolus-Derived Neutrophil Inhibitory Factor and Its Effects on The Development of Lung Injuries-

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In the development of lung injury, the infiltrating neutrophils and their injury-causative agents, such as protease or active oxygen radicals are mainly involved. Most of the therapies have not been effective for those disease states and the prognosis of these patients are still poor.We have focused on the neutrophil inhibitory factors found in the pulmonary alveolus. In a series of these studies, we reported that rat lung surfactant and rat alveolar type II cells directory inhibited human neutrophil superoxide production. We also found another neutrophil inhibitory factors in the soluble fraction of the bronchoalveolar lavage fluids in rats. These inhibitory activities were destroyed by treating the samples at 100ﾟC for 10min, suggesting that inhibition was derived from the protein components. The inhibitory factors were also shown to be different from those previously described, such as superoxide disumutase (SOD) and were expected to be new therapeutic agents for the patients with l … More ung injuries.In the researches in 1996, we have shown that the inhibitory effect was independent of that by surfactant specific proteins, such as SP-A or SP-D.In the next year, we focused on one of the inhibitory cytokines, transforming growth factor-beta (TGF-beta) as the candidate of neutrophil inhibitory factors. We tried the experiments (1) showing whether human TGF-beta can inhibit human neutrophil functions, (2) measuring the TGF-beta concentration in the lung lavage fluids, and (3) neutralizing the inhibitory activities by anti-TGF-beta antibodies. The results, however, were not satisfactory by the reasons of the species difference between human and rats, the high nonspecific adsorbent activity of this cytokine. Although we determined the approximate molecular weight of these inhibitory activities around 200-300 kDa, we were unable to purify these inhibitory proteins since inhibitory activities were lost during the purification procedures. The goal of the present study has not been achieved at this point, but we further need to purify these inhibitory molecules and to establish the specific monoclonal antibody recognizing these molecules. Less