Canadian HealthCare: Smooth muscle hyperplasia

Imatinib is a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia by inhibiting BCR-ABL kinase activity. It can also block other factors, such as c-kit ligand, stem cell factor, and platelet-derived growth factor (PDGF) receptor tyrosine kinase activity. It was reported to block the increase of ASM mass in a mouse asthma model.

Smooth muscle hyperplasia

PDGF receptor is a receptor tyrosine kinase. Its signaling, known as a cell migration inducer, also causes ASMC proliferation. Hirota et al showed its plausibility as an agent of remodeling by demonstrating an increase of ASM mass and cellular proliferation using an adenovirus-mediated PDGF overexpression mouse asthma model.

TGF-b is a pleiotropic cytokine, which was reported to increase in the asthmatic airways. Its expression can be detected in both immune cells and structural cells. In a COPD mouse model, Podowski et al showed the improvement of subepithelial collagen deposition and airway wall thickening by inhibition of TGF-b.

Eotaxin (CCL) is a chemokine that is known for its potent chemoattractant effect for eosinophils. Using a mouse model, Wegmann et al reported that antagonizing CCR, an eotaxin receptor, prevented some features of airway remodeling, goblet metaplasia, subepithelial fibrosis, and increase of number of myofibroblasts.

Based on the pathologic findings, the cellular events occurring in airway remodeling are smooth muscle hyperplasia and hypertrophy, epithelial cell hyperplasia and goblet cell metaplasia, subepithelial fibrosis, and neovascularization. Smooth muscle hyperplasia is inferred by the increase of their proliferation and migration. Asthmatic ASMCs in culture retain the property of more rapid proliferation rates compared with normal ASMC. ASMC migration toward the airway epithelium has been suggested from the findings on proximal asthmatic airway bronchial biopsy samples. It is postulated that ASMC migration may be a contributor to the expansion of smooth muscle bundles.

Physiologic scales and symptoms have been used to assess the clinical states of patients with asthma. Given the fact that asthma and COPD are inflammatory syndromes and complexes of several phenotypes that cause reversible or partial airway narrowing, more detailed classification of the patients and appropriate therapies for each group are necessary. For example, treatment strategies based on monitoring sputum eosinophil counts reduce asthma exacerbations. However, we are lacking specific biomarkers that reflect airway remodeling.

Health Care Mall: Dyspnea

The same descriptors of dyspnea are associated with different diseases, suggesting that these aspects of breathlessness may be shared by similar receptors or neural pathways. (3) Certain diseases are associated with a unique set of descriptors of breathlessness that likely relate to different pathophysiologic mechanisms. (4) The majority of patients report that dyspnea occurs during inspiration, thus implicating the role of the respiratory muscles in the experience of breathlessness. 

 (5) Ethnic and cultural differences are reflected in the words or phrases used by patients to describe dyspnea. (6) Patients differentiate between sensory (intensity) and affective (unpleasant) qualities of breathlessness. (7) Descriptors of dyspnea are related to the intensity level of breathlessness. (8) Patients throughout the world with COPD report similar descriptors of breath-lessness.

Dyspnea

In the present issue of CHCM Pharmacy, Williams and colleagues prospectively evaluated whether descriptors of dyspnea can differentiate between patients with COPD and age-matched healthy individuals. Initially, subjects volunteered relevant words or phrases and then endorsed (selected) up to three statements from the aggregate list to describe “when their breathing was uncomfortable.” Cluster analysis showed that “volunteered” and up to three “endorsed” descriptors of dyspnea could be used to categorize a majority of subjects into their original group classification (COPD or healthy individuals).

In general, only patients with COPD, but not healthy individuals, volunteered affective words such as “frightening,” “worried,” “helpless,” “depressed,” and “awful” to describe their breathing difficulty. These expressions were not included in the list of 15 descriptors used for selection; the phrases in the list include only somatic descriptors of breathlessness (eg, “hard to breathe” and “chest tightness”). Williams and colleagues proposed that these affective descriptions are intended to convey the threat perceived by the patients to their breathing difficulty. These experiences are consistent with the statement by Comroe that “dyspnea. . . involves both perception of the sensation by the patient and his reaction to the sensation.”

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Pneumonia or an elevated temperature (ie > 38.9°C)

Materials and Methods This trial was conducted in 20 US hospital-affiliated EDs. Patients aged 12 to 65 years who presented to the ED with acute asthma were screened by study investigators for trial eligibility. Eligible patients were those with a history of asthma and a FEV₁ of < 70% predicted both at ED entry and 25 min after receiving a single aerosol treatment with 2.5 mg of albuterol. Patients with the following conditions were excluded from the study: history of smoking of > 10 pack-years.

Positive pregnancy test result; a recent history of oral corticosteroid use (ie, > 5 days) or treatment with a leukotriene-modifying drug within 2 weeks of ED entry; a need for intubation before randomization; pneumonia or an elevated temperature (ie, > 38.9°C); chronic lung disease other than asthma; or diabetes mellitus or any other clinically significant medical condition that could affect the required evaluations. 

Additionally, patients had to be willing to stay in the ED for at least 4 h (ie, the ED period) and then to participate in a 28-day outpatient treatment program (Fig 1). The trial was conducted in compliance with the principles of good clinical practice, approval was obtained from each institutional review board, and informed consent was obtained from all patients. 

Trial Design and Treatment At ED entry, patients underwent spirometry and were treated with nebulized albuterol (2.5-mg unit-dose nebules) [Ventolin; GlaxoSmithKline; Research Triangle Park, NC]. Spirometry was repeated 25 min after ED entry, and patients with FEV₁ values still < 70% of predicted were randomized, 1:1:2, respectively, to double-blind, single-dose treatment with zafirlukast, 160 mg (Z160), zafirlukast, 20 mg (Z20) [Accolate; AstraZeneca; Wilmington, DE], or matching placebo. Patients then received a 60-mg po dose of prednisone and a second dose of nebulized albuterol, with additional albuterol administered at 60, 120, and 180 min after ED entry.

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Incidence Rates and HRs for MACEs

Cardiovascular Event Rates According to Cardiovascular Disorders at Baseline Risk factors recorded at baseline included the presence of hypertension, diabetes mellitus, hyperlipidemia, and a history of heart disease (Table 1). Adjudicated event rates were higher in patients with baseline cardiovascular risk factors than in those without baseline cardiovascular risk (Table 4). HRs for MACEs found in patients treated with roflumilast relative to placebo in patients without cardiovascular diseases or risk factors at baseline were lower than in those with cardiovascular comorbid conditions. Adjusting for cardiovascular risk factors at baseline did not materially affect the HR for MACEs. 

Rates and HRs for MACEs

There were significantly fewer MACEs for roflumilast than for placebo in the subgroup of patients with COPD who did not have cardiovascular comorbid conditions at baseline (Table 1). Cardiovascular Event Rates According to Other Factors at Baseline Adjudicated event rates according to age, sex, smoking status, COPD severity, and concomitant long-term pulmonary medication use are shown in Figure 3. HRs were similar across age, sex, and smoking status. There were no significant interactions for COPD severity, concomitant inhaled corticosteroid use, or long-acting b-agonist use. 

However, reductions in MACEs were significant in patients with severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage III), in those using concomitant inhaled corticosteroids, and in those not using long-acting Ь-agonists and not in the corresponding subgroups. Cardiovascular Event Rates According to COPD Exacerbations Subanalyses of the four trials carried out for 1 year demonstrated that exacerbations of COPD were reduced significantly by roflumilast relative to placebo. 

Between patients with and without exacerbations, the proportions with MACEs were similar (1.7% and 1.6%, respectively). Between patients with and without MACEs, the proportions experiencing exacerbations were similar (43.2% and 42.1%, respectively). Table 4—Incidence Rates and HRs for MACEs According to Baseline CV Comorbid Diseases

Patient Group	Roflumilast	Placebo	HR (Roflumilast vs Placebo)	95% CI	P Value
No. patients with CV comorbid conditions	3,584	3,056
Composite MACE	43 (1.2)	51 (1.7)	0.75	0.50-1.14	.185
CV death	27 (0.8)	31 (1.0)	0.72	0.43-1.23	.232
Nonfatal MI	10 (0.3)	12 (0.4)	0.94	0.40-2.20	.893
Nonfatal stroke	6 (0.2)	9 (0.3)	0.55	0.18-1.66	.288
No. patients without CV comorbid conditions	2,979	2,435
Composite MACE	9 (0.3)	25 (1.0)	0.36	0.17-0.77	.009
CV death	8 (0.3)	12 (0.5)	0.65	0.26-1.59	.340
Nonfatal MI	1 (0.0)	10 (0.4)	0.09	0.01-0.70	.021
Nonfatal stroke	0 (0.0)	3(0.1)	0		.996

Data are presented as No. (%), unless otherwise indicated. See Table 3 legend for expansion of abbreviations. “Calculated using Cox proportional hazard model with terms for treatment, age, sex, smoking status, and country pool. Includes ischemic heart disease, type 2 diabetes, dyslipidemia, and hypertension.