The effect of anti-integrin monoclonal antibodies on antigen-induced pulmonary inflammation in allergic rabbits
Introduction
The integrin adhesion molecules are implicated in the migration and activation of inflammatory cells to inflamed lung tissue which is considered central to the pathophysiology of asthma [1], [2].
The principle cell types recruited into the asthmatic lung are the eosinophils and lymphocytes and there is also an increase in the number of mast cells present in the lung. These cells express a variety of integrins, which bind to ligands present on vascular endothelial cells and the tissue matrix, to mediate extravasation and cell migration to inflamed tissues [2].
Two principal integrin families are the α4 and the β2 integrins. The α4 integrin CD49d/CD29 (VLA-4; α4β1) binds endothelial VCAM-1 and tissue matrix fibronectin. Another important α4 integrin is α4β7 which may be involved in binding of eosinophils and lymphocytes to MadCAM-1 in gut associated tissues [3], [4]. The β2 integrin (CD18) forms heterodimers with three distinct α-chain polypeptides, CD11a (LFA-1), CD11b (Mac-1) and CD11c (p150/95). These integrins bind to ICAMs present on vascular endothelial cells.
The adhesion molecule VLA-4 is thought to be important in asthma since it is expressed on eosinophils and T-lymphocytes [2] and more recently on mast cells [5]. Furthermore, expression of the VCAM-1 is increased in tissues from subjects with asthma [6]. Blocking anti-α4 (CD49d) monoclonal antibodies (mAb) have previously been shown to suppress antigen (Ag)-induced pulmonary inflammation in a variety of species including mice [7], [8], rat [9] and guinea-pig [10], [11]. The β2 integrins are also widely expressed on inflammatory cells in asthma and increased expression of ICAM-1 has been shown in asthmatic tissue [12]. Additionally, blocking anti-CD18 (β2) mAbs have also been shown to reduce Ag-induced pulmonary inflammation in guinea-pigs [13] and rabbits [14].
We have also previously reported that the Ag-induced acute bronchoconstriction and eosinophilia is dependent on CD49d (α4) in allergic rabbits [15]. Moreover, we have demonstrated that the eosinophil recruitment parallels the increased expression of VCAM-1 in rabbit lungs following Ag challenge [16]. To further characterise the adhesion molecules involved in the mast cell mediated acute bronchoconstriction and the inflammatory cell recruitment in the allergic rabbit model, we have investigated the effects of blocking mAbs directed against CD49d (α4), CD18 (β2) and α sub-units of CD18, CD11a (LFA-1) and CD11b (Mac-1) on Ag-induced acute airways obstruction and pulmonary inflammation.
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Animals
New Zealand white rabbits (NZW) of either sex (Harlan UK, Ltd) weighing 2.4–3.5 kg at three months of age were used throughout the study. All animals received food and water ad libitum and were housed for at least one week prior to experimentation. The neonatal immunisation of rabbits has been described in detail elsewhere [17]. Briefly, rabbits were injected intraperitoneally (0.5 ml) within 24 h of birth with Alternaria tenuis (Ag) extract (40,000 PNU ml−1) in aluminium hydroxide (Al(OH)3)
Acute bronchoconstriction
Treatment with either the control or anti-integrin mAbs had no effect on baseline lung function values prior to Ag inhalation (RL; 35 ±5 cm H2O l−1 s−1 and Cdyn; 4.0±0.2 ml cm H2O−1).
In control mAb (101.4) treated rabbits, saline challenge caused a small increase (12–15%) in resistance (RL) and fall in dynamic compliance (Cdyn). In contrast, inhaled Ag (A. tenuis) caused a significant 45% increase in baseline RL and a 40% fall in Cdyn in control mAb (101.4) treated rabbits (Fig. 1A and B). The
Discussion
Asthma is a chronic inflammatory condition characterised by the accumulation of pulmonary eosinophils and lymphocytes [26], along with intermittent variable changes in airways obstruction. In allergic asthma, mast cell activation is thought to play a role in the airway obstruction. The integrin adhesion molecules are involved in the trafficking of inflammatory cells from the circulation into the inflamed lung [1], [2] and has also recently been implicated in the acute mast cell degranulation
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