Repeated subacute ozone exposure of inbred mice: airway inflammation and ventilation

The present study was designed to assess the effects of repeated subacute ozone (O3) exposure on pulmonary inflammation and ventilation in two inbred strains of mice differentially susceptible to a single O3 exposure. Susceptible C57BL/6J (B6) and resistant C3H/HeJ (C3) mice were exposed to 0.3 ppm O3 for 48 and 72 h and, after 14 days recovery, both strains were reexposed. Airway inflammation and lung injury were assessed by counting inflammatory cells and measuring total protein content and lactate dehydrogenase (LDH) activity in bronchoalveolar lavage (BAL) returns. Minute ventilation [VE, the product of breathing frequency (f), and tidal volume (VT)] was measured prior to and immediately following each exposure. After the initial exposure, B6 mice developed greater O3-induced increases in total protein, inflammatory cell influx, and LDH activity compared to C3 mice. In normal air, VE was also significantly elevated in B6, but not C3, mice after O3. The hypercapnic f of B6 and hypercapnic VT of C3 mice were significantly altered after O3 exposure. Reexposure to O3 caused a smaller increase in the numbers of macrophages, lymphocytes, epithelial cells, and BAL protein in both strains, and no changes in LDH activity. However, the number of polymorphonuclear leukocytes significantly increased in B6 and C3 mice as compared to the initial O3 exposure. In both strains, the ventilatory responses to normal air or hypercapnia were largely reproducible after O3 reexposure. Results indicated that differential susceptibility to O3-induced inflammation was maintained in B6 and C3 mice with O3 reexposure although the magnitude of the difference was reduced. Results also suggest that the ventilatory responses to O3 in B6 and C3 mice were reproducible with reexposure, and that airway inflammation and ventilation were not codependent.     

Kinase-negative mutants of JAK1 can sustain interferon-gamma-inducible gene expression but not an antiviral state

The receptor-associated protein tyrosine kinases JAK1 and JAK2 are both required for the interferon (IFN)-gamma response. The effects of expressing kinase-negative JAK mutant proteins on signal transduction in response to IFN-gamma in wild-type cells and in mutant cells lacking either JAK1 or JAK2 have been analysed. In cells lacking endogenous JAK1 the expression of a transfected kinase-negative JAK1 can sustain substantial IFN-gamma-inducible gene expression, consistent with a structural as well as an enzymic role for JAK1. Kinase-negative JAK2, expressed in cells lacking endogenous JAK2, cannot sustain IFN-gamma-inducible gene expression, despite low level activation of STAT1 DNA binding activity. When expressed in wild-type cells, kinase-negative JAK2 acts as a dominant-negative inhibitor of the IFN-gamma response. Further analysis of the JAK/STAT pathway suggests a model for the IFN-gamma response in which the initial phosphorylation of JAK1 and JAK2 is mediated by JAK2, whereas phosphorylation of the IFN-gamma receptor is normally carried out by JAK1. The efficient phosphorylation of STAT 1 in the receptor-JAK complex may again depend on JAK2. Interestingly, a JAK1-dependent signal, in addition to STAT1 activation, appears to be required for the expression of the antiviral state.