IL-2 enhances allergic airway responses in rats by increased inflammation but not through increased synthesis of cysteinyl leukotrienes,☆☆,

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Abstract

Background: IL-2 has been shown to increase allergic airway responses in rats. Objective: The purpose of this study was to investigate whether induction of inflammation and enhancement of cysteinyl-leukotriene (cys-LT) synthesis were involved in the augmentation of airway responses caused by IL-2. Methods: Brown Norway rats received human recombinant IL-2 or saline subcutaneously twice a day from day 9 to day 14 after sensitization to ovalbumin (OVA). On day 14, rats underwent either lung lavage or were challenged with an aerosol spray of OVA, the airway responses and biliary excretion of cys-LTs were measured for a period of 8 hours after challenge, and the lung leukocyte numbers were determined after enzymatic digestion of lung tissues. Results: The early response after OVA increased from 184.2% ± 13.5% in the animals receiving saline (n = 10) to 309% ± 51% (baseline lung resistance) in IL-2–pretreated animals (n = 17; P < .05). The late response also increased from 19.6 ± 4.5 (area under the curve of baseline lung resistance vs time) in the animals receiving saline to 37 ± 5.4 after administration of IL-2 ( P < .05). However, IL-2–treated animals had lower levels of biliary cys-LTs during the late response than saline-treated animals but similar levels during the early response. This difference could not be attributed to an increase in LT metabolism, which we assessed by the recovery of 3 H-LTC 4 instilled intratracheally in challenged or unchallenged rats. When compared with control animals, pretreatment with IL-2 increased all cell types retrieved from lung lavage fluid before OVA challenge ( P < .05). After OVA challenge, the total cell yield from lung lavage fluid was also increased, mostly because of an increase in neutrophils ( P < .05). Eosinophils and lymphocytes were greater in the lungs of IL-2–treated than vehicle-treated and OVA-challenged rats ( P < .01), and IL-2–treated rats had a lower CD4 + /CD8 + ratio in the blood after challenge ( P < .001). Conclusion: In conclusion, IL-2 increases early and late responses in rats, and it induces lung inflammation. Altered airway responses are not attributable to an increase in cys-LT production. (J Allergy Clin Immunol 1999;104:145-52.)

Section snippets

Animals and sensitization

Fifty-nine male highly inbred BN rats (Harlan Sprague Dawley) that were 7 to 9 weeks old were studied. All rats were sensitized with OVA by subcutaneous injection of 1 mL of sterile solution containing 1 mg of OVA and 3.5 mg of Al(OH) 3 gel in 1 mL of saline. On the same occasion, 0.5 mL of Bordetella pertussis vaccine containing 6 × 10 9 heat-killed bacilli was injected intraperitoneally into all of the rats except the 18 that underwent studies with lung lavage.

Drugs and chemicals

IL-2 was graciously provided by

Effect of IL-2 on airway responses to OVA

IL-2 caused an increase in the airway responses to OVA (Fig 1 ) .

. Effect of IL-2 on the airway response to OVA. BN rats received either IL-2 (8500 or 30,000 U) or saline (control) subcutaneously twice a day from day 9 to day 14 after sensitization and were challenged with OVA. R L is presented as a percentage of baseline over time in minutes.

The pattern of change in R L was similar in the control and IL-2–treated animals, with the exception that recovery from the early response was incomplete,

DISCUSSION

Pretreatment of BN rats with IL-2 for 4.5 days increased the early and late airway responses after OVA challenge. IL-2 enhanced airway inflammation, as evidenced by an increased cellular return from lung lavage fluid that was characterized by a higher yield of eosinophils and lymphocytes from the S/P after antigen challenge. Although IL-2 did not significantly increase the total cellular return from the tissues of the large airways, it did increase the yield of eosinophils. The mechanism of the

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    Supported by the J. T. Costello Memorial Research Fund, the Research Center of the University of Montreal affiliated Hospitals, and the Medical Research Council of Canada (grant number MA 10381).

    ☆☆

    Reprint requests: Paolo M. Renzi, MD, Meakins Christie Laboratories, 3626 St-Urbain St, Montreal, P.Q., Canada H2X 2P2.

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