Airway Remodeling and Rhinovirus in Asthmatics

Airway remodeling is a characteristic feature of asthma, and refers to the structural changes that are present in the airways of asthmatic individuals. These changes are considered to be a major contributor to the pathophysiology of the episodic airway dysfunction, termed airway hyperresponsiveness (AHR) that is a hallmark of asthma. The traditional paradigm has, until recently, held that airway remodeling occurs after many years of chronic inflammation. However, more recently, studies have confirmed that remodeling changes are observed in children, in some instances even before the formal diagnosis of asthma is established. Moreover, there is now robust evidence to indicate that children with recurrent human rhinovirus (HRV)-induced wheezing episodes are at significantly increased risk of developing subsequent asthma. This has led us to hypothesize that HRV infections play a role in the development and subsequent continued progression of airway remodeling. In support of this paradigm-shifting hypothesis, we have published novel data, both in vitro and in vivo, establishing that HRV infections up-regulate airway epithelial cell production of several important mediators involved in airway remodeling remodeling processes. A potential limitation of the in vivo studies reported by us to date is that these have involved healthy, non-asthmatic research participants studied during naturally-acquired HRV infections. Such studies are subject to seasonal variability and are difficult to perform in well-defined study populations, due to uncertainty regarding the onset of infection and the kinetics of subsequent host inflammatory responses. We therefore plan perform a Phase II clinical trial in which we will perform experimental HRV infections in subjects with mild-moderate asthma and in healthy control subjects. This will allow us to accurately study the kinetics of HRV-induced inflammatory and remodeling responses in a well characterized cohort of asthmatic subjects and compare these outcomes to those in a healthy, non-asthmatic control cohort. The primary study outcome will be to determine if alterations in relevant airway remodeling growth factors differ between healthy controls and asthmatic subjects pre- and post-HRV infection. These growth factors will be assessed in bronchoalveolar lavage fluid (BALF) and endobronchial biopsy tissues and correlated with viral titres in both nasal lavage and BALF. Airway epithelial cells are the primary site of HRV infection, and are the only cell type in which HRV has been detected thus far during in vivo infections. Moreover, there is unequivocal evidence that, following experimental nasal HRV inoculation, virus spreads to infect lower airway epithelial cells, providing a strong biological rationale for the proposed clinical study. HRV only replicate productively in vivo in humans and higher primates and even though rhinoviruses replicate in higher primates (chimpanzees and gibbons), infected animals do not show symptoms. Although two recent publications have reported induction of airway inflammation following exposure of mice to massive doses of unpurified HRV, these responses were transient with little evidence of sustained viral replication. Consequently, we hold the view that HRV only causes relevant infections in vivo in humans and it is for that reason that we continue to focus exclusively on human model systems for all our experimental work. A better understanding of in vivo HRV-induced airway remodeling mediators, and the mechanisms that regulate them, should extend our understanding of the role of HRV infections in the pathogenesis of airway remodeling in asthma. Clinical studies involving the experimental infection of volunteers with rhinovirus have been conducted for more than 40 years. Challenge pools of rhinovirus for these experiments have generally been produced and safety tested according to guidelines published in 1964 and updated in 1992. The challenge pools produced under these guidelines appeared to be safe. Multiple studies have been conducted over this 40-year period in several countries. Dr. Proud has over 20 years of experience in conducting experimental HRV infection protocols. In the 40 years of such studies, it is reasonable to estimate that some 10,000 volunteers have been challenged worldwide to date, and no serious complications attributable to the viral infection have been detected. Moreover, nearly a dozen experimental HRV infection studies have been done in subjects with mild-moderate asthma over the past decade without serious complications. While these studies have contributed substantially to our understanding of rhinovirus-induced asthma symptoms, as well as of host inflammatory and antiviral responses, none have yet looked at the effects of experimental HRV infection on indices of airway remodeling. Therefore, as a natural extension of our current research program and, in keeping with our expertise in HRV-related research, we now plan to perform this experimental rhinovirus infection study. We plan to use a US Food and Drug Administration (FDA) approved Good Manufacturing Practices (GMP)-grade HRV-39 (a gift from Dr. Ronald B. Turner, University of Virginia) for our proposed study. Use of this GMP-grade HRV-39 viral stock ensures compliance with recent regulatory agency requirements which, beginning in 2001, have mandated that HRV preparations used for human inoculation be made under Good Manufacturing Practices (GMP). This proposed clinical study will allow us to address fundamental questions regarding the nature, kinetics and potential mechanisms of upper and lower airway inflammatory responses in subjects with well-controlled mild-moderate asthma and in healthy, non-asthmatic control subjects; a better understanding of these mechanisms may lead to new paradigms in the treatment of virally-induced airway remodeling and asthma exacerbations.