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1.
Front Immunol ; 15: 1371764, 2024.
Article in English | MEDLINE | ID: mdl-38983858

ABSTRACT

Introduction: Environmental exposures and experimental manipulations can alter the ontogenetic composition of tissue-resident macrophages. However, the impact of these alterations on subsequent immune responses, particularly in allergic airway diseases, remains poorly understood. This study aims to elucidate the significance of modified macrophage ontogeny resulting from environmental exposures on allergic airway responses to house dust mite (HDM) allergen. Methods: We utilized embryonic lineage labeling to delineate the ontogenetic profile of tissue-resident macrophages at baseline and following the resolution of repeated lipopolysaccharide (LPS)-induced lung injury. We investigated differences in house dust mite (HDM)-induced allergy to assess the influence of macrophage ontogeny on allergic airway responses. Additionally, we employed single-cell RNA sequencing (scRNAseq) and immunofluorescent staining to characterize the pulmonary macrophage composition, associated pathways, and tissue localization. Results: Our findings demonstrate that the ontogeny of homeostatic alveolar and interstitial macrophages is altered after the resolution from repeated LPS-induced lung injury, leading to the replacement of embryonic-derived by bone marrow-derived macrophages. This shift in macrophage ontogeny is associated with reduced HDM-induced allergic airway responses. Through scRNAseq and immunofluorescent staining, we identified a distinct subset of resident-derived interstitial macrophages expressing genes associated with allergic airway diseases, localized adjacent to terminal bronchi, and diminished by prior LPS exposure. Discussion: These results suggest a pivotal role for pulmonary macrophage ontogeny in modulating allergic airway responses. Moreover, our findings highlight the implications of prior environmental exposures in shaping future immune responses and influencing the development of allergies. By elucidating the mechanisms underlying these phenomena, this study provides valuable insights into potential therapeutic targets for allergic airway diseases and avenues for further research into immune modulation and allergic disease prevention.


Subject(s)
Macrophages, Alveolar , Transcriptome , Animals , Mice , Macrophages, Alveolar/immunology , Macrophages, Alveolar/metabolism , Pyroglyphidae/immunology , Respiratory Hypersensitivity/immunology , Lung/immunology , Disease Models, Animal , Mice, Inbred C57BL , Allergens/immunology , Lipopolysaccharides , Female , Hypersensitivity/immunology
2.
bioRxiv ; 2023 Feb 16.
Article in English | MEDLINE | ID: mdl-36824904

ABSTRACT

The ontogenetic composition of tissue-resident macrophages following injury, environmental exposure, or experimental depletion can be altered upon re-establishment of homeostasis. However, the impact of altered resident macrophage ontogenetic milieu on subsequent immune responses is poorly understood. Hence, we assessed the effect of macrophage ontogeny alteration following return to homeostasis on subsequent allergic airway responses to house dust mites (HDM). Using lineage tracing, we confirmed alveolar and interstitial macrophage ontogeny and their replacement by bone marrow-derived macrophages following LPS exposure. This alteration in macrophage ontogenetic milieu reduced allergic airway responses to HDM challenge. In addition, we defined a distinct population of resident-derived interstitial macrophages expressing allergic airway disease genes, located adjacent to terminal bronchi, and reduced by prior LPS exposure. These findings support that the ontogenetic milieu of pulmonary macrophages is a central factor in allergic airway responses and has implications for how prior environmental exposures impact subsequent immune responses and the development of allergy.

3.
Anesthesiol Res Pract ; 2021: 9002061, 2021.
Article in English | MEDLINE | ID: mdl-34899902

ABSTRACT

BACKGROUND: False assumptions regarding the generalizability of patients' expectations and preferences across different demographic groups may contribute in part to the increased prevalence of negative peripartum outcomes seen among women of color. The intention of this study was to determine preferences and concerns regarding anesthesia care during cesarean delivery in a largely African-American population and to compare them to those obtained in a prior study conducted in a demographically distinct population. METHODS: Women presenting for scheduled cesarean delivery or induction of labor completed a preoperative survey requesting demographic information and the opportunity to rank ten common potential anesthetic outcomes in relation to each other from most to least desirable. Participants were also asked about their biggest fear concerning their anesthetic and their preferences and expectations regarding degree of wakefulness, pain, and other adverse events. Those who underwent cesarean delivery were administered a briefer postoperative survey. We tabulated preference rankings and then compared demographic and outcome data to that obtained in a previous study with a demographically dissimilar population. RESULTS: A total of 73 women completed the preoperative survey, and 64 took the postoperative survey. Pain during and after cesarean delivery was ranked as least desirable outcomes and fear of paralysis was respondents' principal concern with neuraxial anesthesia. Postoperative concerns were similar to preoperative concerns and did not correlate with the frequency with which specific adverse outcomes occurred. These results were consistent with those from the previous study despite the women in this study being more likely to be younger, unmarried, African-American, and less educated than those in the previous investigation. CONCLUSIONS: Patient preference rankings and concerns were remarkably similar to those previously demonstrated despite a number of demographic differences between the two populations, suggesting generalizability of these preferences to a broader obstetric population.

4.
PLoS One ; 16(2): e0247504, 2021.
Article in English | MEDLINE | ID: mdl-33617569

ABSTRACT

BACKGROUND: Increased exposure to Ozone (O3) is associated with adverse health effects in individuals afflicted with respiratory diseases. Surfactant protein-A (SP-A), encoded by SP-A1 and SP-A2, is the largest protein component in pulmonary surfactant and is functionally impaired by O3-oxidation. OBJECTIVE: We used humanized SP-A2 transgenic mice with allelic variation corresponding to a glutamine (Q) to lysine (K) amino acid substitution at position 223 in the lectin domain to determine the impact of this genetic variation in regards to O3 exposure. METHODS: Mice were exposed to 2ppm O3 or Filtered Air (FA) for 3 hours and 24 hrs post-challenge pulmonary function tests and other parameters associated with inflammation were assessed in the bronchoalveolar lavage (BAL) fluid and lung tissue. Additionally, mouse tracheal epithelial cells were cultured and TEER measurements recorded for each genotype to determine baseline epithelial integrity. RESULTS: Compared to FA, O3 exposure led to significantly increased sensitivity to methacholine challenge in all groups of mice. SP-A2 223Q variant mice were significantly protected from O3-induced AHR compared to SP-A-/- and SP-A2 223K mice. Neutrophilia was observed in all genotypes of mice post O3-exposure, however, SP-A2 223Q mice had a significantly lower percentage of neutrophils compared to SP-A-/- mice. Albumin levels in BAL were unchanged in O3-exposed SP-A2 223Q mice compared to their FA controls, while levels were significantly increased in all other genotypes of O3-exposed mice. SP-A 223Q MTECS has significant higher TEER values than all other genotypes, and WT MTECS has significantly higher TEER than the SP-A KO and SP-A 223K MTECS. SIGNIFICANCE: Taken together, our study suggests that expression of a glutamine (Q) as position 223 in SP-A2, as opposed to expression of lysine (K), is more protective in acute exposures to ozone and results in attenuated O3-induced AHR, neutrophilia, and vascular permeability.


Subject(s)
Genetic Variation , Ozone/pharmacology , Pulmonary Surfactant-Associated Protein A/genetics , Airway Resistance/drug effects , Animals , Capillary Permeability/drug effects , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Inflammation/genetics , Mice, Inbred C57BL
5.
Obstet Gynecol Clin North Am ; 48(1): 31-51, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33573789

ABSTRACT

Racism in America has deep roots that impact maternal health, particularly through pervasive inequities among Black women as compared with White, although other racial and ethnic groups also suffer. Health care providers caring for pregnant women are optimally positioned to maintain vigilance for these disparities in maternal care, and to intervene with their diverse skillsets and knowledge. By increasing awareness of how structural racism drives inequities in health, these providers can encourage hospitals and practices to develop and implement national bundles for patient safety, and use bias training and team-based training practices aimed at improving care for racially diverse mothers.


Subject(s)
Ethnicity , Healthcare Disparities , Maternal Health , Maternal Mortality/ethnology , Racism , Black or African American , Delivery, Obstetric/mortality , Female , Hospitals , Humans , Maternal Health Services , Morbidity , Patient Safety , Pregnancy , United States , White People
6.
Anesthesiol Clin ; 38(2): 279-296, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32336384

ABSTRACT

Racism in the United States has deep roots that affect maternal health, particularly through pervasive inequalities among black women compared with white. Anesthesiologists are optimally positioned to maintain vigilance for these disparities in maternal care, and to intervene with their unique acute critical care skills and knowledge. As leaders in patient safety, anesthesiologists should drive hospitals and practices to develop and implement national bundles for patient safety, as well as using team-based training practices designed to improve hospitals that care for racially diverse mothers.


Subject(s)
Healthcare Disparities/ethnology , Maternal Mortality/ethnology , Prenatal Care , Racism , Adult , Black or African American , Anesthesiologists , Female , Humans , Morbidity , Patient Safety , Physician's Role , Pregnancy , Risk Factors , White People
7.
Elife ; 92020 01 28.
Article in English | MEDLINE | ID: mdl-31989925

ABSTRACT

Lung disease causes significant morbidity and mortality, and is exacerbated by environmental injury, for example through lipopolysaccharide (LPS) or ozone (O3). Toll-like receptors (TLRs) orchestrate immune responses to injury by recognizing pathogen- or danger-associated molecular patterns. TLR4, the prototypic receptor for LPS, also mediates inflammation after O3, triggered by endogenous hyaluronan. Regulation of TLR4 signaling is incompletely understood. TLR5, the flagellin receptor, is expressed in alveolar macrophages, and regulates immune responses to environmental injury. Using in vivo animal models of TLR4-mediated inflammations (LPS, O3, hyaluronan), we show that TLR5 impacts the in vivo response to LPS, hyaluronan and O3. We demonstrate that immune cells of human carriers of a dominant negative TLR5 allele have decreased inflammatory response to O3 exposure ex vivo and LPS exposure in vitro. Using primary murine macrophages, we find that TLR5 physically associates with TLR4 and biases TLR4 signaling towards the MyD88 pathway. Our results suggest an updated paradigm for TLR4/TLR5 signaling.


Immune cells in the lung help guard against infections. On the surface of these cells are proteins called TLR receptors that recognize dangerous molecules or DNA from disease-causing microbes such as bacteria. When the immune cells detect these invaders, the TLR receptors spring into action and trigger an inflammatory response to destroy the microbes. This inflammation usually helps the lung clear infections. But it can also be harmful and damage the lung, for example when inflammation is caused by non-infectious substances such as pollutants in the atmosphere. There are several TLR receptors that each recognize a specific molecule. In 2010, researchers showed that the receptor TLR4 is responsible for causing inflammation in the lung after exposure to pollution. Another receptor called TLR5 also helps activate the immune response in the lung. But it was unclear whether this receptor also plays a role in pollution-linked lung damage. Now, Hussain, Johnson, Sciurba et al. ­ including one of the researchers involved in the 2010 study ­ have investigated the role of TLR5 in immune cells from the lungs of humans and mice. The experiments showed that TLR5 works together with TLR4 and helps trigger an inflammatory response to both pollutants and bacteria. Hussain et al. found that people lacking a working TLR5 receptor (which make up 3­10% of the population) are less likely to experience lung inflammation when exposed to pollution or bacterial proteins that activate TLR4. These findings suggest that people without TLR5 may be protected from pollution-induced lung injury. Further research into the role of TLR5 could help develop genetic tests for identifying people who are more sensitive to damage from pollution. This information could then be used to determine the likelihood of a patient experiencing certain lung diseases.


Subject(s)
Lung Injury , Myeloid Differentiation Factor 88 , Signal Transduction , Toll-Like Receptor 4 , Toll-Like Receptor 5 , Animals , Cells, Cultured , Humans , Inflammation/immunology , Inflammation/metabolism , Lung/immunology , Lung/metabolism , Lung Injury/chemically induced , Lung Injury/metabolism , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Polymorphism, Single Nucleotide/genetics , Signal Transduction/genetics , Signal Transduction/immunology , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 5/genetics , Toll-Like Receptor 5/metabolism
9.
Toxicol Sci ; 169(2): 499-510, 2019 06 01.
Article in English | MEDLINE | ID: mdl-30825310

ABSTRACT

Sex differences clearly exist in incidence, susceptibility, and severity of airway disease and in pulmonary responses to air pollutants such as ozone (O3). Prior rodent O3 exposure studies demonstrate sex-related differences in the expression of lung inflammatory mediators and signaling. However, whether or not sex modifies O3-induced airway physiologic responses remains less explored. To address this, we exposed 8- to 10-week-old male and female C57BL/6 mice to either 1 or 2 ppm O3 or filtered air (FA) for 3 h. At 12, 24, 48, and 72 h following exposure, we assessed airway hyperresponsiveness to methacholine (MCh), bronchoalveolar lavage fluid cellularity, cytokines and total protein/albumin, serum progesterone, and whole lung immune cells by flow cytometry. Male mice generated consistent airway hyperresponsiveness to MCh at all time points following exposure. Alternatively, females had less consistent airway physiologic responses to MCh, which were more variable between individual experiments and did not correlate with serum progesterone levels. Bronchoalveolar lavage fluid total cells peaked at 12 h and were persistently elevated through 72 h. At 48 h, bronchoalveolar lavage cells were greater in females versus males. Bronchoalveolar lavage fluid cytokines and total protein/albumin increased following O3 exposure without sex differences. Flow cytometry of whole lung tissue identified dynamic O3-induced immune cell changes also independent of sex. Our results indicate sex differences in acute O3-induced airway physiology responses and airspace influx without significant difference in other injury and inflammation measures. This study highlights the importance of considering sex as a biological variable in acute O3-induced airway physiology responses.


Subject(s)
Ozone/toxicity , Respiratory Hypersensitivity/chemically induced , Acute Disease , Animals , Cytokines/analysis , Female , Immunophenotyping , Male , Methacholine Chloride/pharmacology , Mice , Mice, Inbred C57BL , Progesterone/blood , Sex Characteristics
10.
Am J Physiol Lung Cell Mol Physiol ; 315(5): L787-L798, 2018 11 01.
Article in English | MEDLINE | ID: mdl-30188746

ABSTRACT

Allergic asthma is a major cause of morbidity in both pediatric and adult patients. Recent research has highlighted the role of hyaluronan (HA), an extracellular matrix glycosaminoglycan, in asthma pathogenesis. Experimental allergic airway inflammation and clinical asthma are associated with an increase of shorter fragments of HA (sHA), which complex with inter-α-inhibitor heavy chains (HCs) and induce inflammation and airway hyperresponsiveness (AHR). Importantly, the effects of sHA can be antagonized by the physiological counterpart high molecular weight HA (HMWHA). We used a mouse model of house dust mite-induced allergic airway inflammation and demonstrated that instilled HMWHA ameliorated allergic airway inflammation and AHR, even when given after the establishment of allergic sensitization and after challenge exposures. Furthermore, instilled HMWHA reduced the development of HA-HC complexes and the activation of Rho-associated, coiled-coil containing protein kinase 2. We conclude that airway application of HMWHA is a potential treatment for allergic airway inflammation.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Disease Models, Animal , Hyaluronic Acid/administration & dosage , Inflammation/prevention & control , Pyroglyphidae/pathogenicity , Respiratory Hypersensitivity/prevention & control , Animals , Female , Inflammation/etiology , Male , Mice , Mice, Inbred C57BL , Molecular Weight , Respiratory Hypersensitivity/etiology
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