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Sex-differences in LPS-induced neonatal lung injury.

ABSTRACT: Being of the male sex has been identified as a risk factor for multiple morbidities associated with preterm birth, including bronchopulmonary dysplasia (BPD). Exposure to inflammatory stress is a well-recognized risk factor for developing BPD. Whether there is a sex difference in pulmonary innate immune TLR4 signaling, lung injury and subsequent abnormal lung development is unknown. Neonatal (P0) male and female mice (ICR) were exposed to systemic LPS (5?mg/kg, IP) and innate immune signaling, and the transcriptional response were assessed (1 and 5?hours), along with lung development (P7). Male and female mice demonstrated a similar degree of impaired lung development with decreased radial alveolar counts, increased surface area, increased airspace area and increased mean linear intercept. We found no differences between male and female mice in the baseline pulmonary expression of key components of TLR4-NF?B signaling, or in the LPS-induced pulmonary expression of key mediators of neonatal lung injury. Finally, we found no difference in the kinetics of LPS-induced pulmonary NF?B activation between male and female mice. Together, these data support the conclusion that the innate immune response to early postnatal LPS exposure and resulting pulmonary sequelae is similar in male and female mice.

SUBMITTER: Nguyen L

PROVIDER: S-EPMC6560218 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Sex-differences in LPS-induced neonatal lung injury.

Nguyen Leanna L Castro Odalis O De Dios Robyn R Sandoval Jeryl J McKenna Sarah S Wright Clyde J CJ

Scientific reports 20190611 1

Being of the male sex has been identified as a risk factor for multiple morbidities associated with preterm birth, including bronchopulmonary dysplasia (BPD). Exposure to inflammatory stress is a well-recognized risk factor for developing BPD. Whether there is a sex difference in pulmonary innate immune TLR4 signaling, lung injury and subsequent abnormal lung development is unknown. Neonatal (P0) male and female mice (ICR) were exposed to systemic LPS (5 mg/kg, IP) and innate immune signaling, a ...[more]

PMID: 31186497

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Project description:BackgroundAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) are clinical syndromes characterized by acute lung inflammation, pulmonary edema and hypoxemia, with up to 50% mortality rate without effective pharmacological therapy. Following the acute inflammation, repair and remodeling occurs which in some cases resulting in lung fibrosis. The pathophysiology of ALI/ARDS remains incompletely understood. Lipopolysaccharide (LPS)-induced ALI in mice have been widely used as a model to study human ALI/ARDS. Isthmin 1 (ISM1) is a secreted protein highly abundant in mouse lung. We have previously reported that upon intratracheal LPS instillation, ISM1 expression in the lung is further upregulated. Recently, we also reported that ISM1 is an anti-inflammatory protein in the lung with Ism1-/- mice presenting spontaneous chronic low-grade lung inflammation and obvious emphysema at young adult stage. However, what role ISM1 plays in ALI/ARDS and lung fibrosis remain unclear.MethodsUsing Ism1-/- mice and intratracheal LPS-induced ALI, and local delivery of recombinant ISM1 (rISM1), we investigated the role ISM1 plays in ALI and post-ALI lung fibrosis using flow cytometry, Western blot, antibody array, immunohistochemistry (IHC), immunofluorescent and other histological staining.ResultsWe reveal that ISM1 deficiency in mice led to an intensified acute lung inflammation upon intratracheal LPS challenge, with a heightened leukocyte infiltration including neutrophils and monocyte-derived alveolar macrophages, as well as upregulation of multiple pro-inflammatory cytokines/chemokines including tumor necrosis factor α (TNF-α). Although innate immune cells largely subsided to the baseline by day 7 post-LPS challenge in both wild-type and Ism1-/- mice, Ism1-/- lung showed increased post-ALI fibrosis from day 9 post-LPS treatment with increased myofibroblasts, excessive collagen accumulation and TGF-β upregulation. The heightened lung fibrosis remained on day 28 post-LPS. Moreover, intranasal delivered recombinant ISM1 (rISM1) effectively suppressed LPS-induced acute lung inflammation and ALI, and rISM1 suppressed LPS-induced NF-κB activation in cultured mouse alveolar macrophages.ConclusionTogether with our previous report, this work further established ISM1 as an endogenous anti-inflammation protein in the lung, restraining excessive host inflammatory response to LPS-triggered ALI and suppressing post-ALI lung fibrosis likely through suppressing NF-κB activation and pro-inflammatory cytokine/chemokine production.

Dataset Information

Sex-differences in LPS-induced neonatal lung injury.

Publications

Sex-differences in LPS-induced neonatal lung injury.

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