Perinatal nicotine with or without early life influenza infection leads to lung dysfunction with age.

Obstructive Airway Diseases (OADs) affect millions of people worldwide, and are characterized by chronic inflammation and tissue remodeling in the lung. It has been proposed that the development of OAD is greatly influenced (and perhaps pre-determined) by early life events, such as maternal smoking or a viral infection. However, direct evidence of this is limited and the mechanisms involved remain unclear. Our laboratory previously developed a murine model of perinatal nicotine exposure, and reported that nicotine leads to airway remodeling and decreased pulmonary function in the offspring. We discovered these effects were mediated through the α7 nicotinic acetylcholine receptor (nAChR). Similarly, respiratory viral infections during childhood, such as Influenza A Virus (IAV), have been implicated in the development of OADs in epidemiological and murine studies. We set out to investigate if perinatal nicotine and/or early life IAV infection could promote lung remodeling and long-term pulmonary dysfunction. We employed a previously established murine model for nicotine exposure and a newly developed model for early life IAV infection. Importantly, lung dysfunction was tested at 7-months of age, in which all other studies look at lung dysfunction at earlier times. v We show that both chronic nicotine exposure starting during embryogenesis and continuing until adulthood (but not transient exposure limited to the perinatal period) and early life IAV infection separately are capable of driving lung dysfunction with age. Interestingly, limited differences in lung dysfunction were discovered with chronic exposure and early life IAV infection alone, whereas major lung dysfunctional differences were discovered for transient perinatal nicotine exposure followed by early life IAV infection suggesting a potentiation effect. Abnormalities in lung function were accredited to increased peri-airway collagen deposition and enlarged alveolar structures; the latter appeared due to alveolar simplification during development but also perhaps destruction during aging. We discovered that α7 nAChRs partially mediated these changes. All together, we found that indeed these early life exposures resulted in abnormalities in lung structure and function that persisted into adulthood. This model of nicotine exposure and early life IAV infection in young mice provides a novel tool for studying the impact of these exposures in lung