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Bronchoalveolar lavage of healthy human adults after LPS exposure

ABSTRACT: Rationale: Macrophages are both drivers of dysregulated inflammation and essential for healthy repair following acute lung injury. Distinct subsets of human macrophages have been associated with lung pathology but whether unique cellular programs are causally linked to disease or merely represent a conserved response to tissue damage is unknown. Objectives: We sought to identify the transcriptional heterogeneity and cellular programing of airspace macrophages (AM) during normal lung repair in a human model of self-resolving acute lung injury. Methods: Fifteen subjects underwent bronchoscopic lavage before and at a pre-assigned time point after endobronchial exposure to bacterial endotoxin. Cells from lavage were subjected to single-cell RNA sequencing and a longitudinal assessment of AM programing during resolution of inflammation and lung repair was performed. Measurements and Main Results: We identify transcriptionally distinct subsets of AM present at all time points, in all subjects. We focus on two populations that increase following inflammation, one which aligns closely with classical circulating monocytes (MoAM) and one with interstitial macrophages (IMAM). Comparison of subset-specific markers to those identified in disease states reveals that IMAM express many so-called “pathogenic” macrophage markers during both health and inflammation. Conclusions: By applying a uniform inflammatory stimulus to healthy adults and examining BAL cells obtained at precise time points following inflammation, we construct a time-resolved kinetic of AM transcriptional programing during inflammation and normal lung repair. Our data suggest that IMAM are similar to cells identified at increased frequency in disease states and may reflect a conserved cellular response to tissue injury.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300946 | GEO | 2025/08/14

REPOSITORIES: GEO

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Project description:Toll like receptor 4 (TLR4), an innate immunity gene, is involved in responses to several pulmonary agonists including endotoxin (LPS; Poltorak et al.,1998), ozone (O3 ,Kleeberger et. al., 2001), Pseudomonas aeruginosa (Faure et al, 2004), and hyperoxia (Zhang et al, 2005). TLR4 appears to partially mediate the response to LPS- and O3-induced lung injury, however, TLR4 is protective for prevention of injury in Pseudomonas aeruginosa infection and against acute lung injury (hyperoxia). The mechanism behind this protection is unclear. We previously demonstrated that TLR4 was also protective against BHT-induced chronic inflammation and tumor promotion (Bauer et al, 2005). C.C3H-Tlr4Lps-d (BALBLps-d) mice, congenic for a 10 cM region of C3H/HeJ chromosome 4 that contains Tlr4 (Vogel et al, 1994), have a missence mutation that renders TLR4 dysfunctional. The Tlr4 mutation likely abrogates signaling by disrupting a direct point of contact with other signaling molecules (Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004;4(7):499-511.). Bronchoalveolar lavage fluid (BALF) alveolar macrophages, lymphocytes, and total protein content were significantly elevated in BALBLps-d mice compared to BALB/c (BALB; Tlr4 sufficient) mice following chronic BHT (Bauer et al., 2005). BALBLps-d mice also had a significant increase in tumor multiplicity (60%) over that of BALB mice in response to an MCA/BHT tumor promotion protocol. While this was the first model to demonstrate a protective role for TLR4 in chronic lung inflammation and tumorigenesis, the downstream mechanism regulating this protective response remains unknown. Using Affymetrix microarray analysis followed by GeneSpring and Ingenuity pathway analyses, we herein identified known and novel downstream pathways and their interactions that may be involved in the protective mechanism elicited by TLR4. We therefore hypothesize that these pathways and interactions amongst the genes identified during the tumor promotion/chronic inflammation stage are in part influencing the differential strain response observed during tumorigenesis. Keywords: time course, tumor study Protocol 1 - 3 biological replicates after chronic dosing in each mouse strain Protocol 2 - multiple replicates after MCA/BHT tumor progression model used

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Bronchoalveolar lavage of healthy human adults after LPS exposure

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