K. Frank Austen

Austen insightfully unraveled the biochemical, cellular, and molecular characteristics of the biosynthesis of the cysteinyl leukotrienes (slow-reacting substance of anaphylaxis/SRS-A) and the diversity of the mast cell phenotypes, two key components of allergic and asthmatic inflammation. He defined the local extracellular inactivation of the cysteinyl leukotriene family; the energy-dependent carrier mediate export of LTC4, which gives rise to LTD4 and LTE4; the products and function when the initial substrate is fish oil eicosapentaenoic acid; and the logs greater potency of the cysteinyl leukotrienes relative to histamine for the human airway. He cloned the cDNA for human LTC4, defined the residues R51 and Y93 as essential for the conjugation of LTA4 with reduced glutathione, and characterized the gene at 5q35 distal to the gene cluster for the Th2 cytokines. The basal transcription of this TATA-less gene involved an initiator and a SP-1 site while cell specificity was through tandem motifs for Kruppel-like factors. The validity of Austen''s commitment to this pathway is apparent from the efficacy of inhibitors in the management of patients with bronchial asthma. For the mast cell, Austen discovered that a single gene designated serglycin, encoded the peptide core of secretory granule proteoglycans of hematopietic cells and identified novel chondritin sulfate E or diB proteoglycans as dominant to heparin proteoglycan in T cell-driven mast cells. Eight different mouse secretory granule proteases were cloned, providing the probes that defined on mouse mast cell phenotypes. A new class of counterregulatory receptors was defined on mouse mast cells, and co-ligation of gp49B1 to FceRI was shown to inhibit IgE-mediated activation through recruitment of SHP-1. The co-mitogenic activity of Th2 cytokines for human mast cells highlights the relationship of Th2 cells, submucosal eosinophils, and intraepithelial mast cells a combination that dominates allergic and asthmatic inflammation.