L. Gordon Letts

Intercellular adhesion molecule-1 contributes to pulmonary oxygen toxicity in mice: Role of leukocytes revised

In immature or injured lungs, impaired alveolar gas exchange forces the use of elevated levels of inhaled oxygen to maintain life. But, at high concentrations oxygen induces lung injury, edema, and bronchopulmonary dysplasia, probably by stimulating the generation of reactive oxygen radicals and subsequent neutrophil infiltration. In addition to regulating neutrophil diapedesis, intercellular adhesion molecule-1 (ICAM-1) expression is marked on inflamed alveolar epithelium, suggesting a role for ICAM-1 in oxygen-induced, neutrophil-mediated parenchymal damage. To test this, we evaluated the rat anti-mouse ICAM-1 monoclonal antibody YN 1/1.7 in 2 protocols of oxygen-induced toxicity in adult, male Balb-c mice: ≥95% O2 for 84 hr and ≥95% O2 for 60 hr followed by 48 hr at 21% (ambient) O2. YN1/1.7 treatment partially attenuated the neutrophil infiltration, lung damage (lavage lactate dehydrogenase [LDH] activity) and dysfunction (reductions in respiratory system compliance [Crs] and diffusion capacity of the lungs for carbon monoxide [DLco] in the 84 hr exposure protocol. In the milder 60 hr exposure protocol, YN1/1.7 completely blocked the oxygen-induced lung dysfunction (reductions in Crs and DLco). These results confirm the contribution of leukocytes in the pathogenesis of pulmonary oxygen toxicity and indicate that antagonism of ICAM-1 may provide a therapeutic approach to reducing hyperoxic lung injury and dysfunction.

The role of 5-lipoxygenase products in preclinical models of asthma

BACKGROUNDnThe action of 5-lipoxygenase on arachidonic acid generates potent inflammatory mediators that may contribute to the pathophysiology of asthma.nnnMETHODSnUsing the potent and selective 5-lipoxygenase inhibitor BI-L-239, we have examined the role of 5-lipoxygenase products in three animal models of asthma.nnnRESULTSnIn vitro BI-L-239 inhibited 5-lipoxygenase product generation from human lung mast cells, alveolar macrophages, and peripheral blood leukocytes with a concentration that would provide 50% inhibition values of 28 to 340 nmol/L. A 36-fold selectivity for immunoreactive leukotriene C4 versus immunoreactive prostaglandin D2 inhibition was demonstrated in mast cells. In anesthetized cynomolgus monkeys, inhaled BI-L-239 provided dose-dependent inhibition of the inhaled Ascaris-induced immunoreactive leukotriene C4 release (maximum, 73%; bronchoalveolar lavage [BAL], 20 minutes), late-phase bronchoconstriction (maximum, 41%; +6 to 8 hours), and neutrophil infiltration (maximum, 63%; BAL, +8 hours). In conscious sheep, inhaled BI-L-239 provided dose-dependent inhibition of the inhaled Ascaris-induced late-phase bronchoconstriction (maximum, 66%; +6 to 8 hours) and increase in airway responsiveness (maximum, 82%; carbachol, +24 hours). The acute bronchoconstriction was shortened, and neutrophil infiltration diminished (maximum, 61%; BAL, +8 hours) in this model. Finally in conscious actively sensitized guinea pigs pretreated with pyrilamine and indomethacin, inhaled BI-L-239 attenuated acute bronchoconstriction (maximum, 80%; +5 to 15 minutes), leukocyte infiltration (58%; BAL, +3 days) and increase in airway responsiveness (100%; methacholine, +3 days) induced by three alternate-day ovalbumin inhalations.nnnCONCLUSIONSnIn conclusion, results in these three animal models indicate that 5-lipoxygenase products may be major contributors to the bronchoconstriction (especially late phase), leukocyte infiltration, and airway hyperresponsiveness that characterize asthma.

Effects of single and multiple inhalations of antigen on airway responsiveness in monkeys

Airway hyperresponsiveness is an important and characteristic feature of asthma. In monkeys, we have reported that antigen (Ag) inhalation induces a prolonged airway eosinophilia, that chronic airway eosinophilia is associated with marked airway hyperresponsiveness, and that chronic Ag inhalations induce airway eosinophilia and hyperresponsiveness. In this study we have determined the effects of acute Ag inhalation(s) on airway responsiveness to obtain a protocol for the study of the mechanisms involved. Anesthetized and intubated adult male cynomolgus monkeys with a naturally occurring sensitivity to Ascaris suum extract were studied. Airway responsiveness (provocative concentration of nebulized and inhaled methacholine that induced a 100% increase in respiratory system resistance [Rrs] [PC100]; twofold decrease regarded as significant) and airway cell composition (bronchoalveolar lavage [BAL]) were determined 1 day before and 20 hours after a single inhalation of Ascaris extract, or 3 days before and 3 days after three alternate-day inhalations of Ascaris extract. The single inhalation of Ag (N = 7) caused an acute increase in Rrs (307% +/- 62%), an increase in BAL leukocytes, and a decrease in PC100 in three animals that was moderate (more than eightfold) in two animals. The mean +/- SE change in log PC100 was only -0.25 +/- 0.24. The multiple inhalations of Ag in the same animals caused acute increases in Rrs (178% +/- 48%, 380% +/- 83%, and 331% +/- 63%, respectively), an increase in BAL granulocytes, and a decrease in PC100 in six of seven animals (mean +/- SE change in log PC100 was -1.36 +/- 0.34) that was moderate in two and severe (more than 80-fold) in three animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adhesion molecules in a primate model of allergic asthma: clinical implications for respiratory care

ConclusionPrompted by the realization of the importance of chronic airway inflammation in allergic asthma, recent interest has focused on defining the role of adhesion glycoproteins in the development of airway inflammation and subsequent changes in airway function. Many studies in vitro and in vivo have demonstrated an increased expression of certain adhesion molecules on vascular endothelium, airway epithelium and circulating leukocytes associated with the inflammatory response to allergen. Studies with animal models of allergic asthma have shown the effectiveness of antagonists of adhesion molecules in blocking the development of airway inflammation and changes in airways function. These studies suggest that inhibitors of cellular adhesion molecules may represent a novel form of treatment directed specifically at the chronic airway inflammation characteristic of bronchial asthma.

Adhesion Molecules in Acute and Chronic Lung Inflammation

In the quest to understand the events involved with an inflammatory response, research has focused on understanding the role of single mediators such as leukotrienes, thromboxane, platelet activating factor, histamine, etc. Whereas each of these single mediators undoubtedly contributes to the complexity of disease, illustrating individual pathophysiologic or therapeutic modalities by selectively antagonizing or inhibiting the activity of each has proven difficult. In light of these findings attention has focused on understanding the types of cells and their pattern of migration into inflamed tissue. It is thought that by inhibiting either the presence or function of pro inflammatory cells in the lungs it is possible to eliminate a whole range of potentially adverse mediators and promote homeostasis.

The Role of Cellular Adhesion Molecules in Acute and Chronic Airway Inflammation

The role of pro-inflammatory cells and inflammatory mediators in the pathogenesis of asthma has become a subject of profound investigation. The inflammatory process involves a highly complex series of events occurring at both the tissue and cellular levels in response to a diverse number of stimuli. Of particular interest in recent years has been the up-regulation and enhanced expression of cellular adhesion glycoproteins on vascular endothelium and circulating leukocytes that lead to leukocyte margination, activation, and subsequent migration out of the vessels and into the tissue.