William Zhang, MD

This interview in the latest issue of The Respiratory Report features William Zhang, MD, discussing AM iron accumulation, which may contribute to the well-known phenomenon of AM dysfunction in COPD6.

Investigating COPD Pathogenesis: Abnormal Iron Homeostasis in Alveolar Macrophages

Disruptions in iron metabolism within alveolar macrophages may play a key role in the progression and exacerbation of chronic obstructive pulmonary disease (COPD), according to ongoing research led by William Zhang, MD, Assistant Professor of Medicine at Weill Cornell Medicine. His research aims to better understand the biological mechanisms underlying COPD and address gaps that currently limit the development of targeted therapies.

 that is powered by the American Lung Association Research Institute, on his team’s current research in this area.

Zhang and his team used murine models of cigarette smoke exposure and single-cell RNA sequencing to investigate how dysregulated iron metabolism in alveolar macrophages contributes to COPD pathogenesis and exacerbation risk. He found that cigarette smoke induces iron loading in these immune cells, impairing their function, and that disrupting iron regulation may reduce emphysema development but could also weaken infection response. He also discussed proof-of-concept studies in humans the team is conducting.

"To get rid of an important protein that breaks down ferritin and allows the cell to retrieve iron when it needs to, especially when macrophages are fighting infection, I think probably also hampers them to some extent in this infection model. So, I think that the biology behind this is is more complex than we initially hypothesized and not so straightforward," Zhang said.

To learn more about Zhang's research, view the interview above or read his contribution to the third issue of The Respiratory Report here:

Abnormal Iron Homeostasis in Alveolar Macrophages: Implications for COPD Pathogenesis

Videos

William Zhang, MD, has found that disruption of AM iron homeostasis from smoke may potentiate respiratory infections.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death from non-communicable diseases worldwide

. Although cigarette smoke (CS) exposure is known to trigger COPD development, many other biological aspects of COPD pathogenesis are unknown, preventing the development of personalized therapies that target specific mechanistic endotypes. 

We had previously shown that there are elevated levels of iron and iron proteins in the airways of smokers and subjects with COPD which associate with clinical COPD parameters including exacerbation frequency

. The source of these iron biomarkers is likely airspace macrophages (AMs), with various studies showing that AMs from smokers and COPD patients are overloaded with iron and can release iron 

. We hypothesized that this AM abnormal iron metabolism may be a critical driver of COPD pathobiology, and specific to this proposal, that AM iron accumulation contributes to the well-known phenomenon of AM dysfunction in COPD

, resulting in an increased risk for infection and infection-triggered COPD exacerbation.

We replicated CS-induced AM iron loading using a murine model of CS exposure and showed that at the transcriptomic and proteomic levels that there is dysregulation of critical iron metabolic proteins. We then utilized single cell RNA-sequencing and identified unique subpopulations of macrophages which have this iron dysregulated signature. Interestingly, this iron signature is accompanied by the differential expression of critical genes related to AM identity and immune function, suggesting that iron dysregulation have consequences for these cells beyond iron metabolism alone. This supports our hypothesis that disruption of AM iron homeostasis from smoke may potentiate respiratory infections.

To test this hypothesis, we developed a transgenic mouse model that is depleted of an important iron regulatory protein, nuclear coactivator 4 (NCOA4). NCOA4 has indispensable roles in sensing cellular iron levels and degrading the iron storage protein ferritin to retrieve iron in times of high iron requirements

. AM NCOA4 depletion abates CS-induced AM iron accumulation, and we are in the process of completing our image analysis of inflated lung sections from long-term (6-8 months) CS-exposed AM NCOA4-depleted and control mice to determine whether NCOA4 depletion alone is sufficient to deter emphysema development. 

One of the major differences between murine COPD models and human COPD is that COPD in patients progresses in a stepwise fashion in the form of exacerbations. To mimic this, we exposed mice to short (8-12 weeks) periods of smoke and then instilled them with 

 as a second hit to model infection-associated exacerbation. Although mice with AM NCOA4 depletion seemed initially to have improved survival from 

 infection, with more replicate experiments it does not seem that they are protected. This highlights the critical importance of maintaining iron homeostasis as while CS-induced iron overload may have adverse effects on macrophage function, the inability to access ferritin-stored iron during an acute infection may limit AMs energetically and metabolically, preventing efficient bacterial clearance

This work has been presented at the American Thoracic Society (ATS) International Conference. We have completed all experiments in the murine component of this project and are currently at the manuscript preparation stage and expect to submit this work for review later this year. Consistent with the focus of our laboratory, during the funding period of this project we published 2 additional manuscripts that centers on the effect of CS on the AM inflammatory response

We are in the process of translating some of our murine findings back to the bedside. We showed in a proof-of-concept study that we could use deferiprone, an iron chelator, to reduce intracellular iron levels in AMs obtained from bronchoalveolar lavage in smokers but not in subjects with COPD

. Whether this difference is due to fundamental biological differences or due to inadequate dosing and bioavailability is the subject of ongoing studies. 

We are also finalizing our manuscript that evaluates AMs transcriptomically in smokers and subjects in COPD in the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, with interesting findings replicating the findings in our murine transcriptomic studies. This work has already been presented at ATS and should be ready for submission in the next few months.

Zhang has no relevant disclosures to report.

1. Harikrishnan S, Jeemon P, Mini GK, Thankappan KR, Sylaja P. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. 

. 2018;392(10159):1736-1788. doi:10.1016/S0140-6736(18)32203-7

2. Zhang WZ, Oromendia C, Kikkers SA, et al. Increased airway iron parameters and risk for exacerbation in COPD: an analysis from SPIROMICS. 

. 2020;10(1):10562. doi:10.1038/s41598-020-67047-w

3. Wesselius LJ, Flowers CH, Skikne BS. Alveolar macrophage content of isoferritins and transferrin. Comparison of nonsmokers and smokers with and without chronic airflow obstruction. 

. 1992;145(2 Pt 1):311-316. doi:10.1164/ajrccm/145.2_Pt_1.311

4. Wesselius LJ, Nelson ME, Skikne BS. Increased release of ferritin and iron by iron-loaded alveolar macrophages in cigarette smokers. 

. 1994;150(3):690-695. doi:10.1164/ajrccm.150.3.8087339

5. Philippot Q, Deslée G, Adair-Kirk TL, et al. Increased iron sequestration in alveolar macrophages in chronic obstructive pulmonary disease. 

. 2014;9(5):e96285. doi:10.1371/journal.pone.0096285

6. Belchamber KBR, Singh R, Batista CM, et al. Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages. 

. 2019;54(4). doi:10.1183/13993003.02244-2018

7. Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. 

. 2014;509(7498):105-109. doi:10.1038/nature13148

8. Soares MP, Hamza I. Macrophages and iron metabolism. 

. 2016;44(3):492-504. doi:10.1016/j.immuni.2016.02.016

9. Salih MM, Robinson EK, Malekos E, et al. LincRNA-Cox2 Regulates Smoke-induced Inflammation in Murine Macrophages. 

. 2023;68(5):511-522. doi:10.1165/rcmb.2022-0413OC

10. Faherty L, Zhang WZ, Salih MM, et al. Transcriptomic analysis reveals distinct effects of cigarette smoke on murine airspace and bone-marrow derived macrophages. 

. 2024;25(1):322. doi:10.1186/s12931-024-02939-3

11. Kim K, Zhang WZ, Kikkers SA, et al. Use of the iron chelator deferiprone to restore function in BAL fluid macrophages in smoking and chronic obstructive pulmonary disease. 

. 2023;68(4):458-462. doi:10.1165/rcmb.2022-0372LE

Articles

Chronic obstructive pulmonary disease (COPD) is a leading cause of death, with cigarette smoke (CS) exposure being a major trigger. Elevated iron levels in airspace macrophages (AMs) of smokers and COPD patients are linked to disease exacerbation. Research using murine models shows that CS-induced iron dysregulation in AMs affects immune function and may increase infection risk. Depleting nuclear coactivator 4 (NCOA4) in mice reduces iron accumulation but may impair bacterial clearance. Translational studies explore iron chelation in humans, with ongoing research to understand biological differences in COPD.