Eosinophilic infiltration of the airway mucosa and lumen is characteristic of the late asthmatic response. Activated eosinophils release enzymes and mediators that can damage bronchial epithelium (eg, major basic protein, eosinophil cationic protein), induce smooth muscle contraction, enhance microvascular permeability, increase airway hyperreactivity, and contribute to airway wall remodeling.1,2 However, reducing eosinophilia alone in patients with asthma does not abolish the airflow limitation or airway hyperreactivity, which emphasizes the multifactorial nature of asthmatic inflammation.1, 3
Th2 lymphocytes direct ongoing inflammation by releasing specific cytokines and chemokines. Release of IL-4 is particularly important. This cytokine promotes Th2 differentiation, isotype switching of B cells to produce IgE, expression of vascular cellular adhesion molecule 1 (VCAM1, a regulator of inflammatory cell chemotaxis), and the expression of various receptors on mast cells and leukocytes.1
Macrophages and neutrophils are found in the airways during the late reaction, but their numbers are variable and usually lower than eosinophils and lymphocytes.1, 2
The recruitment of inflammatory cells to the airway mucosa is directed by various mediators, which are produced by airway cells and inflammatory cells (eg, eosinophils by eotaxin, IL-5, RANTES; macrophages by MCP-3, MCP-4; neutrophils by IL-8). Vascular adhesion molecules such as VCAM-1, ICAM-1, and E-selectin assist in transmigration of inflammatory cells from the blood vessels into the tissue. Survival factors (eg, GM-CSF) released in situ prolong the inflammatory response.1,2
The cells and mediators involved in asthmatic inflammation represent a normal repair process to injury. However, chronically, the process produces abnormal structural alterations. The characteristic features of this “tissue remodeling” are angiogenesis, thickening of the basement membrane, fibrosis, and smooth-muscle hypertrophy—specifically, the characteristics reported in the early autopsies of fatal asthma.1,4
Constitutive elements of the airway wall contribute to remodeling. Fibroblasts produce collagen, reticular and elastic fibers, and the proteoglycan and glycoprotein components of the extracellular matrix. These cells can grow and differentiate into other cells, including smooth-muscle cells. Myofibroblasts, in turn, can produce collagen, fibronectin, and laminin (components of the extracellular matrix), as well as growth factors that promote angiogenesis and smooth-muscle hypertrophy. Bronchial epithelial cells produce profibrogenic growth factors that encourage myofibroblast activation. Mature airway smooth-muscle cells may be an important source of proinflammatory cytokines and growth factors, thereby perpetuating the remodeling process.1,4
The physiologic consequences of asthmatic inflammation are airflow obstruction and airway hyperreactivity that produce the characteristic symptoms associated with asthma. 5,2 Thus, the signs and symptoms of asthma are multifactorial in origin—involving inflammatory cell infiltration and activation, mediator release, bronchial smooth-muscle contraction, edema, thickening of the airway wall, increased mucus secretion, and enhanced sensitivity of sensory nerves. All increase airway resistance and reduce expiratory airflow.1
References:
1. Blaiss MS, Kaliner MA, Valovirta EJ, Canonica GW, Baena-Cagnani CE, Dahl R, et al. GAPP Survey: Patient Education an Patient-Physician Communications – Global Findings, oral presentation at the American College of Allergy, Asthma and Immunology Annual Meeting. 2005. www.gappsurvey.org.
2. Guest JF, Davie AM, Ruiz FJ, Greener MJ. Switching asthma patients to a once-daily inhaled steroid improves compliance and reduces healthcare costs. Prim Care Respir J 2005;14:88–98.
3. O’Connor B, Kilfeather S, Cheung D, Sips P, Blagden M, Kafe H, et al. Treatment of moderate to severe asthma with ciclesonide: a long-term investigation over 52 weeks. Eur Respir J 2002;20:406s.
4. Kanniess F, Richter K, Bohme S. Effect of inhaled ciclesonide on airway responsiveness to inhaled AMP, the composition of induced sputum and exhaled nitric oxide in patients in mild asthma. Pulm Pharmacol Ther 2001;14:141–147.
5. Leung SY, Eynott P, Nath P, Chung KF. Effects of ciclesonide and fluticasone propionate on allergen-induced airway inflammation and remodeling features. J Allergy Clin Immunol 2005;115:989–996.