Early Postnatal Secondhand Smoke Exposure Disrupts Bacterial Clearance and Abolishes Immune Responses in Muco-Obstructive Lung Disease

Abstract

Secondhand smoke (SHS) exposure has been linked to the worsening of ongoing lung diseases. However, whether SHS exposure affects the manifestation and natural history of imminent pediatric muco-obstructive airway diseases such as cystic fibrosis remains unclear. To address these questions, we exposed transgenic (-Tg) mice to SHS from postnatal day (PND) 3-21 and lung phenotypes were examined at PND22. Although a majority of filtered air (FA)-exposed -Tg (FA-Tg) mice successfully cleared spontaneous bacterial infections by PND22, the SHS-exposed -Tg (SHS-Tg) mice failed to resolve these infections. This defect was associated with suppressed antibacterial defenses, i.e., phagocyte recruitment, IgA secretion, and Muc5b expression. Whereas the FA-Tg mice exhibited marked mucus obstruction and responses, SHS-Tg mice displayed a dramatic suppression of these responses. Mechanistically, downregulated expression of IL-33, a stimulator of type II innate lymphoid cells, in lung epithelial cells was associated with suppression of neutrophil recruitment, IgA secretions, responses, and delayed bacterial clearance in SHS-Tg mice. Cessation of SHS exposure for 21 d restored previously suppressed responses, including phagocyte recruitment, IgA secretion, and mucous cell metaplasia. However, in contrast with FA-Tg mice, the SHS-Tg mice had pronounced epithelial necrosis, alveolar space consolidation, and lymphoid hyperplasia; indicating lagged unfavorable effects of early postnatal SHS exposure in later life. Collectively, our data show that early postnatal SHS exposure reversibly suppresses IL-33 levels in airspaces which, in turn, results in reduced neutrophil recruitment and diminished response. Our data indicate that household smoking may predispose neonates with muco-obstructive lung disease to bacterial exacerbations.

Secondhand smoke alters arachidonic acid metabolism and inflammation in infants and children with cystic fibrosis

“…In our study, SHSe was associated with decreased macrophage-mediated bacterial killing of the common CF pathogen MRSA as well as increased clinical acquisition of P. aeruginosa and S. maltophilia. Our data support recent work that demonstrated early postnatal SHSe in a murine muco-obstructive airway model alters immune function and disrupts bacterial clearance of P. aeruginosa 46. Smoke exposure has been previously shown to augment expression of MRSA virulence factors in non-CF murine models,47 48 and impact phagocytosis of P. aeruginosa in CF49 and non-CF cells in a CFTR-dependent manner 50.…”

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice

“…Briefly, bronchoalveolar lavage fluid (BALF) was harvested from the right lung. Recovered BALF was processed and analyzed for total and differential cell counts by routine methods ( 19 ). Unlavaged left lung lobes were fixed in 10% neutral buffered formalin (NBF) and used for preparation of slides for histopathological evaluation.…”

Immunopathology of Airway Surface Liquid Dehydration Disease

“…IL-33 has also been linked to the activation of ILC2s that also release Th2-associated cytokines [104]. IL-33 levels are elevated in the juvenile Scnn1b -Tg+ mice [105]. Secondhand-smoke exposure to Scnn1b -Tg+ mice results in diminished IL-33 expression and BALF levels, which is strongly associated with diminished MCM and reduced expression of MCM-associated genes [105].…”

“…IL-33 levels are elevated in the juvenile Scnn1b -Tg+ mice [105]. Secondhand-smoke exposure to Scnn1b -Tg+ mice results in diminished IL-33 expression and BALF levels, which is strongly associated with diminished MCM and reduced expression of MCM-associated genes [105]. Further investigation on the mice with a genetic deletion of IL-33 on an Scnn1b -Tg+ background will confirm the role of IL-33 in the manifestation of mucoobstructive responses.…”