Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A(2).
BACKGROUND
The pathophysiology of asthma involves the action of inflammatory/allergic lipid mediators formed following membrane phospholipid hydrolysis by phospholipase A(2) (PLA(2)). Cysteinyl leukotrienes are considered potent inducers of bronchoconstriction and airway remodelling. Ovalbumin (OVA) induced bronchoconstriction in rats is associated with increased secretory PLA(2) (sPLA(2)) activation and cysteinyl leukotriene production, together with suppression of cytosolic PLA(2) and prostaglandin E(2). These processes are reversed when the animals are pretreated systemically with an extracellular cell impermeable sPLA(2) inhibitor which also suppresses the early allergic reaction to OVA challenge. In this study we examine the capacity of the sPLA(2) inhibitor to ameliorate inflammatory and allergic manifestations (early and late bronchoconstriction) of OVA induced allergic bronchitis in rats when the inhibitor was administered by inhalation to confine it to the airways.


METHODS
Rats sensitised with OVA were treated with the sPLA(2) inhibitor hyaluronic acid-linked phosphatidyl ethanolamine (HyPE). The rats were divided into four groups (n = 10 per group): (1) naïve controls (no sensitisation/no treatment); (2) positive controls (sensitisation + challenge with OVA inhalation and subcutaneous injection of 1 ml saline before each challenge; (3) sensitisation + challenge with OVA and HyPE inhalation before every challenge; and (4) sensitisation + challenge with OVA and treatment with subcutaneous dexamethasone (300 mug) before each challenge as a conventional reference. Another group received no treatment with HyPE during the sensitisation process but only before or after challenge of already sensitised rats. Pulmonary function was assessed and changes in the histology of the airways, levels of cysteinyl leukotrienes in BAL fluid, and the production of nitric oxide (No) and tumour necrosis factor alpha (TNFalpha) by BAL macrophages were determined.


RESULTS
Inhalation of HyPE markedly suppressed OVA induced early and late asthmatic reactions as expressed by bronchoconstriction, airway remodelling (histology), cysteinyl leukotriene level in BAL fluid, and production of TNFalpha and NO by BAL macrophages. OVA induced bronchoconstriction in sensitised non-pretreated rats was also inhibited by inhalation of HyPE either before or after the challenge.


CONCLUSIONS
These findings confirm the pivotal role of sPLA(2) in the pathophysiology of both the immediate allergic response and the inflammatory asthmatic process. Control of airway sPLA(2) may be a new therapeutic approach to the treatment of asthma.
Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel 91120.
D
D
Shoseyov
H
H
Bibi
S
S
Offer
O
O
Schwob
M
M
Krimsky
M
M
Kleiman
S
S
Yedgar
D000280:Administration, Inhalation; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001798:Blood Proteins / Q000627:therapeutic use*; D001991:Bronchitis / Q000139:chemically induced* / Q000188:drug therapy; D010047:Ovalbumin / Q000009:adverse effects*; D051381:Rats; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000188:drug therapy
D015415:Biomarkers; D001798:Blood Proteins; C400481:PLIalpha; D010047:Ovalbumin