Synergistic Environmental Exposures and the Airways Capturing Complexity in Humans An Underappreciated World of Complex Exposures

Paradoxically, the vast majority of research models intended to understand the relationship between exogenous exposures and lung disease are reduced to a single inhalant. This approach is understandable given the practical challenges of investigation, but it is problematic in terms of translation to the real-world human condition. Furthermore, use of data from such models can lead to underestimation of effect, which may adversely influence regulatory imperatives to protect public health based on the most robust information. Efforts to incrementally introduce layers of complexity to observational and experimental systems have revealed pathophysiology previously hidden within simplified models. Capturing the effects of co-exposure to traffic-related air pollution and allergens is a paradigmatic example and illustrates the influence of co-exposures across a plethora of clinical and subclinical end points within the respiratory tract. From DNA methylation in the epithelium, to inflammatory mediators and allergen-specific antibodies in the airway, to airflow limitation and symptoms, the addition of a common second exposure induces profound changes. In addition, genetic variation significantly alters the product of these relationships, and capturing multidimensional interactions may reveal susceptible populations who are particularly affected by these exposures and may merit focused measures for protection. Collectively, better modeling, and ultimately deeper knowledge, of these complex relationships has important implications for personalized health and prevention, development and refinement of pharmacologic agents, and public health responses to climate change and the staggering burden of pollution-driven disease worldwide.