Production by Lung Hyaluronidases

Hyaluronan is the natural substrate of hyaluronidases, a family of enzymes (54,55) which are discussed in a separate chapter of this book. At least two hyaluronidases are expressed in the lung. They are HYAL1 (56) and HYAL2 (57), which was first described as a product of lung fibroblasts (58) and is expressed in many tissues. Both these enzymes are lysosomal enzymes and they degrade HA differently than testicular hyaluronidase and provide a large piece of approximately 20 kDa. The genes HYAL1, -2 and -3 are located on the chromosomal region 3p21. This region is deleted in many small cell lung cancer lines. In fact, these genes were known as LuCa-1, -2 and -3 before it was realized that hyaluronidases could result from their expression (57). Another peculiarity concerning the lung relates to HYAL2. Rai et al. (59) expressed HYAL2 in NIH 3T3 cells and could not detect hyaluronidase activity, whereas a construct of HYAL1 in the same cell system did produce hyaluronidase. Furthermore, using other cell systems they describe HYAL2 as a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for Jaagsiekte sheep retrovirus. This retrovirus causes a contagious lung cancer in sheep. These data suggest a broader role for HYAL2 in biological systems. Perhaps, there are isoforms of HYAL2 which are expressed only in response to differentiation signals or after injury and whose products have activities under physiological conditions which are unrelated to its function in the lysosome.

The content of both HA and hyaluronidase in the chick embryo lung change with development (60), and in humans HA is higher in fetal lung than it is after birth or in adult lung (61). Hyaluronidase activity also changes, showing a rapid increase in rat lung immediately after birth (62). Presumably, the removal of HA is necessary to lower the water content of the lung, with which HA has a direct correlation (8,9), in order to facilitate breathing in air.

Under normal conditions hyaluronidases proceed to depolymerize HA in predictable ways and they are tightly regulated. We have shown this to be true for hamster lungs by measuring both HA and hyaluronidase in individual, normal lungs. A plot of total hyaluronidase against total HA for the individual animals gave points that clustered around a narrow range (Bray and Turino, unpublished). Interestingly, not only HA but hyaluronidase also is increased in the lung after bleomycin injury (13) and after oxygen injury (62) but the concept of a wellregulated process does not apply. One factor that leads to this difference is random degradation of HA to lower molecular weight fragments by reactive oxygen (63) and nitrogen species (64) that have been generated as a result of the injury.

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