Postnatal episodic ozone results in persistent attenuation of pulmonary and peripheral blood responses to LPS challenge

Abstract

Early life is a dynamic period of growth for the lung and immune system. We hypothesized that ambient ozone exposure during postnatal development can affect the innate immune response to other environmental challenges in a persistent fashion. To test this hypothesis, we exposed infant rhesus macaque monkeys to a regimen of 11 ozone cycles between 30 days and 6 mo of age; each cycle consisted of ozone for 5 days (0.5 parts per million at 8 h/day) followed by 9 days of filtered air. Animals were subsequently housed in filtered air conditions and challenged with a single dose of inhaled LPS at 1 yr of age. After completion of the ozone exposure regimen at 6 mo of age, total peripheral blood leukocyte and polymorphonuclear leukocyte (PMN) numbers were reduced, whereas eosinophil counts increased. In lavage, total cell numbers at 6 mo were not affected by ozone, however, there was a significant reduction in lymphocytes and increased eosinophils. Following an additional 6 mo of filtered air housing, only monocytes were increased in blood and lavage in previously exposed animals. In response to LPS challenge, animals with a prior history of ozone showed an attenuated peripheral blood and lavage PMN response compared with controls. In vitro stimulation of peripheral blood mononuclear cells with LPS resulted in reduced secretion of IL-6 and IL-8 protein in association with prior ozone exposure. Collectively, our findings suggest that ozone exposure during infancy can result in a persistent effect on both pulmonary and systemic innate immune responses later in life.

Innate Immune Response to LPS in Airway Epithelium Is Dependent on Chronological Age and Antecedent Exposures

“…We do not yet know if age-dependent proinflammatory cytokine synthesis by airway epithelium corresponds to differential respiratory pathogen susceptibility in vivo. However, our previous work has shown that a single LPS aerosol dose administered to juvenile animals results in pulmonary and systemic neutrophilia within 6 hours after exposure, suggesting that innate immune function is sufficient within this age group (31).…”

“…Newborn male rhesus monkeys were housed under high-efficiency particulate air (HEPA) filtered air conditions, as previously described, and evaluated at 1 year of age (31). A subset of animals received a single aerosolized dose of 25,000 EU in PBS via facemask.…”

Early Life Wildfire Smoke Exposure Is Associated with Immune Dysregulation and Lung Function Decrements in Adolescence

“…Peripheral blood mononuclear cells (PBMCs) were prepared as previously described (17). PBMCs were cultured in 96-well tissue culture plates with AIM-V medium (Invitrogen, Carlsbad, CA) at a concentration of 2 3 10 5 cells/100 ml at 37 8 C in 5% CO 2 .…”

“…Studies in animal models have provided supportive data on immune modulation by air pollution exposure during early life. We have previously reported that peripheral blood cells from juvenile monkeys experimentally exposed to episodic ozone during the first 6 months of life produced significantly reduced levels of proinflammatory cytokines when challenged in vitro with Toll-like receptor (TLR) ligands (17).…”

Why primate models matter

“…For example, perinatal environmental tobacco smoke exposure in infant monkeys results in altered immune cytokine profiles and airway innervation [Yu et al, ]. The health effects of environmental exposures can persist long after the exposure has ended, as evidenced in a study by Maniar‐Hew et al [], in which early life ozone exposures resulted in attenuation of innate immune responses in mature monkeys. Nonhuman primate models of allergic airways disease have been in existence for over 40 years, exploiting both a naturally occurring parasitic infection in the wild ( Ascaris spp .)…”