1993). Using a rigid-tube bronchoscope, the bronchial biopsies were taken under local anaesthesia from two different airway levels: (a) inside the right upper lobe bronchus, and (b) at the opening of the right middle lobe (Laitinen et al. 1993). Preparations of the specimens thereby obtained were completed for light as well as electron microscopy; the researchers also used slot grids 1 x 2 mm which facilitated photography of a large area of the thin sections and analysis through an application of a graphic Autocad software program (Laitinen et al. 1993). In the 14 subjects with newly diagnosed asthma, Laitinen and his associates identified an increase in the numbers of mast cells (p < 0.001), eosinophils (p < 0.05), lymphocytes (p < 0.05), and macrophages (p < 0.05) in the epithelium compared to those found in the control subjects. According to Laitinen and his associates, "In the lamina propria, these asthmatic patients had more eosinophils (p < 0.001), lymphocytes (p < 0.001), macrophages (p < 0.001), and plasma cells (p < 0.001) than did the control subjects. We conclude that, in asthma, an airway inflammatory process is present even at a clinically early stage of the disease. In the asthmatic airways, there are signs of a general inflammatory response caused by more than one cell type" (1993, p. 697).

Based on their observation that there remains a dearth of timely studies that have evaluated the asthmatic airway in childhood, Coku-ra?, Seckin, Camcio-lu, Sarimurat and Aksoy (2001) assessed the histopathological changes that take place in the bronchi of children with moderate asthma using light and electron microscopy. These researchers used bronchial biopsy specimens taken from 10 children who suffered from moderate asthma (n = seven boys; three girls) of mean (SD) age 9.3 (3.8) years (range 5-14); the specimens were analyzed using both light and electron microscopy (Coku-ra? et al. 2001). According to these researchers, "Patients had not had a respiratory infection for at least one month and they had not been treated with steroids or sodium cromoglycate for four weeks before the study. Bronchoscopy was performed under general anaesthesia using a Karl Storz rigid paediatric bronchoscope. Biopsy materials were stained with uracyl acetate and lead citrate and evaluated under a Zeiss-10 electron microscope and light microscope" (Coku-ra? et al. 2001, p. 25).

Based on their light and electron microscopic analysis of the specimens, Coku-ra? And his associates found thickening and hyalinization of the basement membrane in nine of the subjects; in addition, in some cases, the ciliated epithelial cells exhibited loss of cilia (Coku-ra? et al. 2001). In addition, these researchers report that overactive fibroblasts were identified consistently throughout the samples of all ten subjects and six of the subjects were shown to have degranulating mast cells and lymphocyte infiltration in the submucosa; however, eosinophils was identified in just one biopsy sample (Coku-ra? et al. 2001). Based on their findings, these researchers conclude that, "Children with moderate asthma develop bronchial inflammation similar to the reaction observed in adults. However, in our study the inflammation was rich in lymphocytes rather than eosinophils" (Coku-ra? et al. 2001, p. 26).

Bronchial epithelial inflammation

According to Zhao, Vaszar, Qiu, Shi and Kao (2000), "Bronchial epithelial cell expression of inflammatory cytokines and growth factors contributes to the airway inflammation that is characteristic of asthma, chronic bronchitis, and bronchiectasis. Structural changes can develop in airways because of the chronic inflammation in cystic fibrosis or atypical mycobacterial pulmonary disease or because of chronic allograft rejection after lung transplantation, which can manifest as obliterative bronchiolitis" (p. 958). Drugs that are administered either systemically or topically can, in some cases, provide suppression of inappropriate airway inflammation and therapeutic benefits in diseases such as asthma and chronic bronchitis; certain pharmacological preparations may also serve to diminish the airway destruction that occurs in bronchiectasis and obliterative bronchiolitis (Zhao et al. 2000).

An early study by Konradova, Hlouskova and Tomanek (1977) examined the ultrastructure of the respiratory passages epithelium of young children, adolescents as well as older adults who suffered from repeated or chronic respiratory disease using material obtained as a small excision during bronchoscopy. The findings were classified into four categories as follows based on the character of the ultrastructural changes found in the epithelium. In large bronchi, the following was found:

1. A completely unaltered pseudostratified columnar ciliated epithelium;

2. A pseudostratified columnar epithelium with various signs of pathological alteration;

3. An altered pseudostratified columnar epithelium with first ultrastructural signs of the development of squamous metaplasia; and,

4. A developed stratified squamous epithelium (Konradova et al. 1977).

Based on their analysis of these findings,...

1977). According to these researchers, "These patients were classified into the second or at most into the third group. The observation of fully developed squamous metaplasia is reserved to older patients with longer history of chronic respiratory disease" (Konradova et al. 1977, p. 270).
A somewhat later study by Heino, Juntunen-Backman, Leijala, Rapola and Laitinen (1990) investigated the ultrastructural findings in biopsies from the main carina of seven children and adolescents who had experienced a chronic cough for a minimum of 3 months; all of the adolescent subjects also had a history of early lower respiratory illness. The seven subjects in this study experienced their initial lower respiratory illness between birth and the age of 7 years (range, 5 to 11 years) (Heino et al. 1990). According to these researchers, "The cross-sectional area of the epithelium was quantified by point counting for the percentage area of intercellular spaces denoting edema, and the numbers of both inflammatory cells (leukocytes, including eosinophils, and mast cells) and ciliated cells" (Heino et al. 1990, p. 428).

The children and adolescent subjects (not including the single subject who used steroid inhalers) exhibited almost 17- and more than sevenfold increases in the mean area of intercellular spaces as well as the number of inflammatory cells per epithelial area, respectively; the subjects also were shown to have an almost 300% decrease in the mean number of ciliated cells per epithelial area compared with the biopsy specimens from the orifice of the right upper lobe bronchus of two healthy adults (Heino et al. 1990).

In sum, Heino and his associates note that, "In the children, the increase in inflammatory cells (greater than 91% were lymphocytes) was more prominent in the children with two lower respiratory illnesses before the age of 1 year" (p. 429). The findings of the Heino et al. study indicate a close relationship between early lower respiratory illness onset and subsequent epithelial inflammation during chronic cough. The researchers add that it is not possible to rule out allergic mechanisms in the epithelial inflammation because all of the subjects exhibited, either alone or in combination, indications of atopia, positive family history of allergic rhinitis or asthma, and eosinophils or mast cells in the epithelium (Heino et al. 1990).

Finally, according to Lynch, "The relationship between irritant chemical exposure and induction of asthma attacks in asthmatics is well established. Irritant chemical exposure causes bronchial epithelium injury. Persons with asthma are more susceptible to irritant and volatile organic chemicals than nonasthmatics and show greater bronchial hyperresponsiveness to irritant exposures than nonasthmatics" (2000, p. 911).

Remodeling

A number of studies in recent years have examined the role of various factors in the airway remodeling associated with asthma. In this regard, Siddiqui and Martin report that, "Airway remodeling in asthma is a complex process that involves structural changes in virtually all tissues of the airway wall. The histologic changes to the airways consist of epithelial proliferation and goblet cell differentiation, subepithelial fibrosis, airway smooth muscle growth, angiogenesis, matrix protein deposition, gland hyperplasia and hypertrophy, and nerve proliferation" (2008, p. 540).

In addition, cytokines, chemokines, and growth factors from inflammatory cells and structural cells have all been shown to contribute to airway remodeling (Siddiqui & Martin 2008). Not surprisingly, complex interactions among the various signaling pathways involve matrix metalloproteinases that are necessary for the release of the growth factor (Siddiqui & Martin 2008). Based on their research, Siddiqui and Martin conclude that, "The physiologic consequences of remodeling are airway hyperresponsiveness from airway smooth muscle growth and mucus hypersecretion from gland and goblet cell hyperplasia. Airway stiffening is a probable contributor to airway hyperresponsiveness through attenuation of the transmission of potently bronchodilating cyclical stress to the ASM during breathing" (2008, p. 541).

According to Kuramoto, Nishiuma, Kobayashi, Yamamoto, Kono, Funada, Kotani, Sisson, Simon and Nishimura, "The airway remodeling that occurs in asthma is characterized by an excess of extracellular matrix (ECM) deposition in the submucosa, hyperplasia/hypertrophy of smooth muscle, goblet cell metaplasia, and accumulation of fibroblasts/myofibroblasts" (2008, p. 73). In addition, the urokinase-type plasminogen activator (uPA)/plasmin system take part in pericellular proteolysis; this plasminogen activator has the capability of degrading matrix components in a direct fashion as well as being able to activate latent proteinases and growth factors (Kuramoto et al. 2008).

In their…