About

William A. Altemeier, M.D., is a board-certified physician specializing in pulmonary and respiratory disease care, with a focus on critical care medicine and smoking-related chronic lung disease. He is a professor of Pulmonary, Critical Care, and Sleep Medicine and Medicine at the University of Washington, and also serves as an adjunct professor of Pathology. Dr. Altemeier is an affiliate investigator at the Fred Hutchinson Cancer Research Center. His research interests include transcriptional regulation during acute lung injury. He earned his M.D. at Vanderbilt University and is board certified in Critical Care Medicine and Pulmonary Disease. Dr. Altemeier is actively involved in clinical care at the General Pulmonary Clinic at UW Medical Center and Fred Hutchinson Cancer Center, and he strives to create active partnerships with his patients to achieve the best possible outcomes. Outside of his professional work, he enjoys reading, bicycling, and hiking.

Research topics

• Internal medicine
• Medicine
• Pathology
• Biology
• Immunology
• Cardiology
• Anesthesia
• Intensive care medicine

Selected publications

• Secreted phospholipase A2 group X regulates peripheral sensitization to allergen

  JCI Insight · 2026-03-12

  articleOpen access

  The molecular mechanisms responsible for the "atopic march" of allergic skin disease to allergic airway disease are incompletely understood. Secreted phospholipase A2 group X (sPLA2-X) is implicated in human asthma and modulates airway hyperresponsiveness (AHR) and inflammation in murine models of allergic asthma. We developed a complete proteolytic allergen model of dermal sensitization followed by airway challenge to mimic the "atopic march" and examined the role of sPLA2-X in regulating peripheral allergen sensitization, AHR, and airway inflammation. Pla2g10-/- mice receiving both house dust mite (HDM) peripheral sensitization and airway challenge had attenuated AHR relative to WT mice and lower airway eosinophils. Transgenic C57BL/6 hPLA2G10 mice (only expressing the human sPLA2-X gene) receiving treatment with a small molecule inhibitor of sPLA2-X (ROC0929) during the dermal sensitization phase demonstrated attenuated AHR and a reduction HDM-specific tissue-resident memory CD4+ T cells in the lung. Thus, sPLA2-X acts as an endogenous adjuvant to facilitate allergic sensitization in the periphery, which leads to AHR and airway inflammation following inhalation of the allergen. These results provide proof of concept that inhibition of sensitization in the periphery with a sPLA2-X inhibitor modulates subsequent allergen-induced airway dysfunction.

  PublisherOA PDFDOI

• Myeloid-derived Secreted Phospholipase A2 Group X Modulates Airway Hyperresponsiveness and Eosinophilic Inflammation in T2 Predominant and Mixed Inflammation Models of Asthma

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article1st authorCorresponding

  Abstract Rationale. Secreted phospholipase A2 group X (sPLA2-X) is increased in the airways of individuals with asthma, and higher levels correlate with airway hyperresponsiveness (AHR). We have previously shown that global deletion of Pla2g10, the gene that expresses sPLA2-X, markedly attenuates AHR, eosinophils and type-2 cytokines in the airways in a T2-predominant allergic model of asthma. In human airways, macrophages and epithelial cells are the primary sources of sPLA2-X, but the contribution of epithelial- or macrophage/monocyte-derived sPLA2-X to the pathogenesis of asthma remains unclear. Here we examined the contribution of macrophage/monocyte-derived sPLA2-X to airway dysfunction and inflammation in models of T2-predominant allergic, T2-predominant non-allergic, and mixed T2 and non-T2 inflammation models of asthma. Methods. Macrophage/monocyte deletion of Pla2g10 was achieved with Lyz2-Cre+/+; Pla2g10fl/fl mice and compared to littermate control mice lacking Cre expression. Three different models were used: 1) a T2-predominant allergic model, using house dust mite (HDM) sensitization and challenge, 2) a T2-predominant non-allergic model, using IL-33 intratracheal exposure; and 3) mixed T2 and non-T2 inflammation model, using HDM with complete Freund's adjuvant (CFA) for peripheral sensitization followed by HDM challenge. Outcome measures were AHR to methacholine and airway leukocyte populations determined by multi-spectral flow cytometry. Results. Mice lacking Pla2g10 expression in myeloid cells had a small but significant reduction in AHR and airway eosinophils in the T2-predominant allergic model (Fig 1A-B) and the mixed T2 and non-T2 inflammation model (Fig 1C-D). In contrast, there was no difference between mice lacking myeloid Pla2g10 and control mice in response to multiple challenges with IL-33. Conclusions. Myeloid-derived sPLA2-X contributes to AHR and eosinophilic inflammation in models of allergic inflammation involving T2-predominant and mixed inflammation, but this effect is not directly mediated through IL-33 in isolation. As IL-33 is a key mechanism leading to T2 inflammation, these results suggest that myeloid-derived sPLA2-X contributes to allergic airway inflammation through both T2 and non-T2 mechanisms.

  PublisherDOI

• Airway Epithelial Responses to Human Rhinovirus A16 Infection Are Differentially Regulated by the Presence of Monocytes

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract Rationale: Recruited, monocyte-derived macrophages are implicated in asthma and are present in the airways of individuals with asthma but their role in regulating inflammatory responses relevant to asthma remains incompletely understood. Human rhinovirus (RV) infections are key triggers for asthma exacerbations and are classically driven by primary infection of airway epithelial cells (AECs). Here we examine AEC responses to RV infection in the presence of peripheral blood monocytes. Methods: Primary AECs were obtained from children with asthma (n=11) and healthy children (n=10), differentiated at air-liquid interface, and cocultured with monocytes derived from the peripheral blood of a single healthy donor (Figure 1A). After infection with RV serogroup-A16 (RV16) for 48 hours, cells were harvested and RNA isolated for high-throughput transcriptomic analysis. Results: AECs infected with RV16 in the presence or absence of monocytes shared 3458 differentially expressed genes (DEGs) (Figure 1B). This shared response was positively enriched in pathways related to anti-viral response, response to type I and type II interferons, and T cell recruitment, and negatively enriched in pathways associated with ciliary function. RV16-infected AECs cocultured with monocytes showed 1047 distinct DEGs (462 upregulated, 585 downregulated), enriched in pathways related to monocyte trafficking, NK cell cytotoxicity, and regulation of IL-13 production. Finally, 1684 DEGs were distinct to RV16-infected cultured alone (727 upregulated, 957 downregulated) and were enriched in pathways related to IL-15-mediated signaling as well as eosinophil and neutrophil migration. The effects of AEC donor phenotype were small relative to the effects of viral infection and the presence of monocytes. There were no significant differences in RV16 counts in AECs based on the presence or absence of monocytes. Conclusion: There are considerable differences in the epithelial response to viral infection when monocytes are present, several of which are implicated as critical mechanisms of airway inflammation in asthma.

  PublisherDOI

• Single Nuclei Versus Single Cell RNA Sequencing in a Murine Model of Bleomycin-induced Lung Injury

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract RATIONALE: Single cell (SC) RNA sequencing has emerged as a powerful tool for studying individual cell populations in complex tissues. However, this technique involves time consuming steps and extensive sample manipulation, which may compromise data integrity and limit its application in certain contexts. Single nuclei (SN) RNA sequencing is an alternative methodology that bypasses some of these technical challenges, but its performance in diverse disease models is not well characterized. Here, we compare the performance of SC and SN RNA sequencing in a murine model of bleomycin-induced lung injury. METHODS: For the SN dataset, mice were challenged with intratracheal bleomycin (1.3 U/kg) and lungs were harvested at days 0, 7, 14 and 21 after injury. Nuclei from the whole lungs were extracted and labeled using combinatorial indexing. Dimensionality reduction, clustering and annotation was performed using the package monocle3 for R. For the SC dataset, sequencing data was retrieved from Gene Expression Omnibus public repository (GSE141259). Mice were treated with bleomycin (2 U/kg) and lungs harvested at days 0, 7, 14 and 21 after injury. After tissue digestion, cells were labeled using Dropseq microfluidic devices. Both datasets were integrated using the RPCA method from the Seurat package. RESULTS: A total of 103,200 nuclei were retrieved from SN sequencing, with an average of 25,800 nuclei per timepoint. The SC dataset is comprised of 29,297 cells with an average of 5,270 cells per timepoint. Integration of both datasets showed good alignment of most populations (Figures A and B), although the SN dataset had unique representation of some populations such as pericytes, neuroendocrine cells and basal cells. The study of cell population ratios showed a more balanced representation in the SN dataset, with the SC dataset favoring immune populations and with a limited representation of the mesenchymal compartment (Figure C). Both datasets capture similar changes in cell populations as consequence of bleomycin injury, including an expansion of the macrophage population, the appearance of a Krt8+/Cdkn1a+ alveolar transitional state and a fibrotic fibroblast phenotype. CONCLUSIONS: SN RNA sequencing offers a valid alternative to SC RNA sequencing in the context of bleomycin-induced lung injury and provides better representation of non-immune cell populations, which may be particularly beneficial for investigators interested in studying less common epithelial and mesenchymal cell populations.

  PublisherDOI

• Secreted Phospholipase A2 Group X Regulates Peripheral Sensitization to Allergen

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract Rationale: The molecular mechanisms responsible for the “atopic march” of allergic skin disease to allergic airway disease are incompletely understood. Secreted phospholipase A2 group X (sPLA2-X) is elevated in the airways of individuals with asthma and mice lacking sPLA2-X (Pla2g10-/-) have attenuated airway hyperresponsiveness (AHR) and inflammation in an allergic airway sensitization and challenge model. However, exogenous sPLA2-X also acts an adjuvant for an allergen-specific type-2 immune response that leads to airway dysfunction upon challenge with antigen. Here we examine the role of sPLA2-X in a complete proteolytic allergen model of dermal sensitization followed by airway challenge. Methods: Balb/c WT and Pla2g10-/- mice received intradermal sensitization with house dust mite (HDM) followed by oropharyngeal challenge with HDM (Figure 1A). We measured AHR to methacholine and assessed inflammation in BAL and lung tissue using spectral flow cytometry. Transgenic C57BL6 hPLA2G10 mice (only expressing the human sPLA2-X gene) underwent the same protocol but received treatment with a small molecule inhibitor of sPLA2-X (ROC0929) during the dermal sensitization phase. In addition, the number of allergen-specific CD4+ T-cells in lung tissue was assessed using MHC class II tetramers. Results: After receiving both HDM peripheral sensitization and airway challenge, Pla2g10-/- mice have attenuated AHR relative to WT mice (Figure 1B) and lower airway eosinophils (Figure 1C). C57BL6 hPLA2G10 mice receiving ROC0929 therapy during the sensitization phase demonstrated attenuated AHR (Figure 1D) and a reduction in dust mite-specific CD4+ T-cells in the airways (Figure 1E). Conclusions: sPLA2-X acts as an endogenous adjuvant to facilitate allergic sensitization in the periphery, which leads to AHR and airway inflammation following inhalation of the allergen. These results provide proof of concept that inhibition of sensitization in the periphery with a sPLA2-X inhibitor has a meaningful effect on subsequent allergen-induced airway dysfunction.

  PublisherDOI

• Immunomodulation of the Innate Host Response by Mesenchymal-Derived Versican during Influenza A Virus Infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-02

  preprintOpen access

  ABSTRACT Viral and bacterial lung infections place a significant burden on public health. Versican, an extracellular matrix (ECM) chondroitin sulfate proteoglycan, coordinates the innate immune response in multiple experimental models. Versican’s potential as an immunomodulatory molecule makes it a promising therapeutic target for controlling the host’s immune response to lung infection. However, versican’s contribution to lung inflammation, injury, and immune cell activity during influenza A virus (IAV) infection represents a critical knowledge gap. To address our central hypothesis that mesenchymal-derived versican is pro-inflammatory and enhances the innate immune response to IAV infection, we generated a tamoxifen-inducible mouse deficient in mesenchymal-derived versican (B6. Col1a2-Cre ERT+/- /Vcan tm1.1Cwf , Col1a2/Vcan -/- ). We report that mesenchymal-derived versican plays a critical role in neutrophil, monocyte, and dendritic cell migration into the lungs and airways early in IAV infection. Intriguingly, mesenchymal-derived versican deficiency had the most substantial negative impact on neutrophil emigration into the lungs. We found that neutrophils were less adhesive to the ECM of Col1a2/Vcan -/- mouse lung fibroblasts (mLFs), which had a significant decrease in versican compared to wild-type mLFs. Additionally, Col1a2/Vcan -/- mLFs treated with poly(I:C) in vitro have reduced cell-associated hyaluronan. These findings suggest that fibroblast-derived versican is necessary for adhesion to lung fibroblasts by neutrophils as they transit into the lung interstitium and airways from the pulmonary vasculature. Our findings demonstrate that mesenchymal-derived versican is a key regulator of the early host immune responses to IAV. NEW & NOTEWORTHY We report the novel finding that mesenchymal-derived versican is critical for neutrophil, monocyte, and dendritic cell migration into the lungs and airways early in influenza A virus infection. Additionally, a differentiated neutrophil-cell line is less adherent to versican-deficient fibroblasts, and versican-deficient fibroblasts have significantly reduced cell-associated hyaluronan (HA) content in vitro . These findings suggest that mesenchymal-derived versican and cell-associated HA are necessary for the adhesion of neutrophils and monocytes to lung fibroblasts.

  PublisherOA PDFDOI

• Pressure Points: Endothelial Responses to Shear Stress and Pressure in Health and Pulmonary Arterial Hypertension

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-02

  preprintOpen access

  Background: Hemodynamic forces exert a profound influence on endothelial signaling and, when abnormal, contribute centrally to human vascular disease. Pulmonary arterial hypertension (PAH) is characterized by both hemodynamic derangement and pulmonary arterial endothelial cell (PAEC) dysfunction. Despite importance in disease initiation and progression, the combined effects of shear and pressure forces on PAEC biology remain incompletely understood, particularly in the context of PAH. Methods: ) shear stress under either low or elevated (60 mmHg) pressure. After 24 hours, we assessed cellular morphology and performed transcriptomic analysis via bulk RNA sequencing, incorporating analyses of PAH subtype and donor sex. Results: Morphologically, PAECs (n=18 donors) aligned with flow under high, but not low, shear, and alignment was not significantly altered by disease state or pressure. As expected, shear stress fundamentally reorganized the PAEC transcriptome. The "dose-response" to increasing shear differed across biological pathways in six statistically significant patterns. Increasing shear led to divergence in transcription between control and PAH cells, particularly in pathways involved in immune activation, stress signaling, and vascular remodeling, with subtype differences also observed. Pressure had modest effects on transcription, with CHD-PAH PAECs notably displaying pressure-induced stress and inflammatory signaling. We identified sexual dimorphism in the endothelial shear response, including that male cells under shear enriched for proliferative and angiogenic pathways and female cells for fatty acid metabolism and stress responses. Conclusions: We provide a systems-level overview of how shear and pressure shape PAEC transcription, revealing divergent responses across disease state, PAH subtype, and donor sex. These findings highlight the need for further investigation into mechanosensitive pathways in PAH as potential novel therapeutic targets.

  PublisherOA PDFDOI

• Regulation of Versican Expression in Macrophages is Mediated by Canonical Type I Interferon Signaling via ISGF3

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-14 · 1 citations

  preprintOpen accessSenior author

  Growing evidence supports a role for versican as an important component of the inflammatory response, with both pro- and anti-inflammatory roles depending on the specific context of the system or disease under investigation. Our goal is to understand the regulation of macrophage-derived versican and the role it plays in innate immunity. In previous work, we showed that LPS triggers a signaling cascade involving TLR4, the Trif adaptor, type I interferons, and the type I interferon receptor, leading to increased versican expression by macrophages. In the present study, we used a combination of chromatin immunoprecipitation, siRNA, chemical inhibitors, and mouse model approaches to investigate the regulatory events downstream of the type I interferon receptor to better define the mechanism controlling versican expression. Results indicate that transcriptional regulation by canonical type I interferon signaling via the heterotrimeric transcription factor, ISGF3, controls versican expression in macrophages exposed to LPS. This pathway is not dependent on MAPK signaling, which has been shown to regulate versican expression in other cell types. The stability of versican mRNA may also contribute to prolonged versican expression in macrophages. These findings strongly support a role for macrophage-derived versican as a type I interferon-stimulated gene and further our understanding of versican's role in regulating inflammation.

  PublisherOA PDFDOI

• Inter-alpha-trypsin inhibitor (IαI) and hyaluronan modifications enhance the innate immune response to influenza virus in the lung

  Matrix Biology · 2024-01-15 · 16 citations

  article
  PublisherDOI

• Mast Cell Immune Responses to Primary Infection With Human Rhinovirus A16 Are Differentially Regulated by the Airway Epithelium

  2024-04-30

  article
  PublisherDOI

Recent grants

• NIH Grant K08HL071020

  NIH · $629k · 2008

• Impact of versican deficiency on the innate immune response to influenza virus

  NIH · $3.1M · 2017–2023

• NIH Grant R01HL086883

  NIH · $2.2M · 2014

• NIH Grant F32HL010003

  NIH · $127k

• PDGFR-beta+ stromal cells as critical regulators of immune response to tissue injury

  NIH · $1.7M · 2015–2020

Frequent coauthors

• Gustavo Matute‐Bello

  University of Washington

  50 shared

• W. Conrad Liles

  University of Washington

  38 shared

• Peter M. Vietze

  Montclair State University

  34 shared

• Charles W. Frevert

  University of Washington

  31 shared

• Sina A. Gharib

  University of Washington Medical Center

  30 shared

• Teal S. Hallstrand

  University of Washington

  30 shared

• Scott E. Sinclair

  Government of Manitoba

  30 shared

• Kathryn B. Sherrod

  Vanderbilt University

  29 shared

Labs

• UW Medicine Pulmonary and Respiratory Disease CarePI

Education

• M.D.

  Vanderbilt University School of Medicine

  1992

• Bachelor of Engineering, Chemical Engineering/Biomedical Engineering

  Vanderbilt University

  1986