Alveolar macrophages are the front-line defenders of the lungs.1

They perform functions that are essential to lung health and homeostasis, including2-4:

  • Phagocytosing infectious and toxic debris
  • Maintaining surfactant homeostasis
  • Activating epithelial repair
  • Modulating host immune response

Many respiratory pathologies, including COVID-19, pneumonia, and influenza, subvert alveolar macrophage function and polarization in various ways during pathogenesis1,5,6

Alveolar macrophages in pathogenesis7

Dysfunctional alveolar macrophage activity can result in further damage and inflammation in the lungs.1

Epithelial Alveolar "Niche"

GM-CSF=granulocyte-macrophage colony-stimulating factor.

Agents that can modulate macrophage polarization during respiratory illness have shown therapeutic potential in preclinical and clinical investigation7–9

References: 1. Allard B, Panariti A, Martin JG. Alveolar macrophages in the resolution of inflammation, tissue repair, and tolerance to infection. Front Immunol. 2018;9:1777. 2. Cakarova L, Marsh LM, Wilhelm J, et al. Macrophage tumor necrosis factor-alpha induces epithelial expression of granulocyte-macrophage colony-stimulating factor: impact on alveolar epithelial repair. Am J Respir Crit Care Med. 2009;180(6):521-532. 3. Byrne AJ, Mathie SA, Gregory LG, et al. Pulmonary macrophages: key players in the innate defence of the airways. Thorax. 2015;70(12):1189-1196. 4. Gordon S, Plüddemann A. Tissue macrophages: heterogeneity and functions. BMC Biol. 2017;15(1):53. 5. Tay MZ, Poh CM, Rénia L, et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20(6):363-374. 6. Fan EKY, Fan J. Regulation of alveolar macrophage death in acute lung inflammation. Respir Res. 2018;19(50):1-13. 7. Rösler B, Herold S. Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia—a new therapeutic strategy? Mol Cell Pediatr. 2016;3(1):29. 8. Halstead ES, Umstead TM, Davies ML, et al. GM-CSF overexpression after influenza a virus infection prevents mortality and moderates m1-like airway monocyte/macrophage polarization. Respir Res. 2018;19(1):3. 9. Unkel B, Hoegner K, Clausen BE, et al. Alveolar epithelial cells orchestrate DC function in murine viral pneumonia. J Clin Invest. 2012;122(10):3652-3664.

Therapeutic modulation of alveolar macrophages is leading to advances in the management and treatment of respiratory illness.1-4

A variety of cytokines and other environmental factors can influence alveolar macrophage activity, representing potential drug targets for novel therapies in lung injury and illness.1-4

The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) has been one of the most studied modulatory approaches to date because it’s essential for the production, differentiation, and survival of alveolar macrophages. Extensive preclinical research demonstrates the critical role of GM-CSF in pulmonary homeostasis and host defense.3,5,6

In GM-CSF–deficient mice, alveolar macrophages are dysfunctional and contribute to major pulmonary defects such as3,5,7:

  • Surfactant accumulation resulting in pulmonary alveolar proteinosis (PAP)
  • Impaired pathogen clearance
  • Reduced T-cell antigen recognition
  • Increased susceptibility to microbial infections
  • Reduced epithelial proliferation
  • Sustained loss of barrier function

In contrast, GM-CSF overexpression in mice confers significant improvements in lung function and immune response, including3,8:

  • Protection against lethal infections
  • Expansion and activation of alveolar macrophages
  • Enhanced antimicrobial activity of alveolar macrophages
  • Reduced alveolar damage and lung injury after infection

Administration of exogeneous GM-CSF improved outcomes following infection in murine models and implicates its therapeutic potential in humans3,6,9-11

  • After infection with lethal influenza, including the pandemic H1N1 strain, intranasal GM-CSF conferred a 100% survival rate, rapid host immune response, and reduced viral burden
  • During influenza A virus infection, GM-CSF prevented mortality from an acute respiratory distress syndrome (ARDS)-like illness, improved survival against secondary bacterial pneumonia, and stabilized lung mechanical parameters
  • In severe influenza virus pneumonia, intratracheal application of GM-CSF induced a return to tissue homeostasis, supported repair and restoration of epithelial injury, and improved host defense

Findings from numerous preclinical studies underlie the rationale for clinical investigation of GM-CSF in patients with severe respiratory illnesses3,6,10

References: 1. Byrne AJ, Mathie SA, Gregory LG, et al. Pulmonary macrophages: key players in the innate defence of the airways. Thorax. 2015;70(12):1189-1196. 2. Gordon S, Plüddemann A. Tissue macrophages: heterogeneity and functions. BMC Biol. 2017;15(1):53. 3. Rösler B, Herold S. Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia—a new therapeutic strategy? Mol Cell Pediatr. 2016;3(1):29. 4. Wynn TA, Chawla A, Pollard JW. Origins and hallmarks of macrophages: development, homeostasis, and disease. Nature. 2013;496(7446):445-455. 5. Cakarova L, Marsh LM, Wilhelm J, et al. Macrophage tumor necrosis factor-alpha induces epithelial expression of granulocyte-macrophage colony-stimulating factor: impact on alveolar epithelial repair. Am J Respir Crit Care Med. 2009;180(6):521-532. 6. Unkel B, Hoegner K, Clausen BE, et al. Alveolar epithelial cells orchestrate DC function in murine viral pneumonia. J Clin Invest. 2012;122(10):3652-3664. 7. Mathias B, Szpila BE, Moore FA, et al. A review of GM-CSF therapy in sepsis. Medicine (Baltimore). 2015;94(50):e2044. 8. Subramaniam R, Barnes PF, Fletcher K, et al. Protecting against post-influenza bacterial pneumonia by increasing phagocyte recruitment and ROS production. J Infect Dis. 2014;209(11):1827-1836. 9. Huang F-F, Barnes PF, Feng Y, et al. GM-CSF in the lung protects against lethal influenza infection. Am J Respir Crit Care Med. 2011;184(2):259-268. 10. Halstead ES, Umstead TM, Davies ML, et al. GM-CSF overexpression after influenza a virus infection prevents mortality and moderates m1-like airway monocyte/macrophage polarization. Respir Res. 2018;19(1):3. 11. Umstead TM, Hewage EK, Mathewson M, et al. Lower respiratory tract delivery, airway clearance, and preclinical efficacy of inhaled GM-CSF in a post-influenza pneumococcal pneumonia model. Am J Physiol Lung Cell Mol Physiol. 2020;318(4):L571-L579.

Ongoing clinical research continues to demonstrate the therapeutic potential of human recombinant GM-CSF (rhGM-CSF) in patients with acute lung illness.1,2

In a randomized, double-blind, placebo-controlled, multicenter, phase 2 trial, intravenous GM-CSF was well tolerated in patients with ALI/ARDS (N=130)3*

No serious adverse events clearly associated with use of GM-CSF

No difference in incidence of serious adverse events with GM-CSF vs placebo

No increase in inflammatory cytokine levels with GM-CSF vs placebo

GM-CSF treatment conferred a greater number of organ-failure–free days and improved 28-day mortality, though results did not reach statistical significance due to the small sample size3

*The primary endpoint was days alive and breathing without mechanical ventilatory support within the first 28 days after randomization, which did not reach statistical significance.3

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In a small trial of patients with pneumonia-associated ARDS who failed to improve despite treatment measures, compassionate use of inhaled GM-CSF (n=6) improved clinical outcomes vs historical controls (n=4)4

Improved oxygenation
(P=0.0035)

Increased lung compliance
(P=0.0787)

Improved morbidity
(P=0.036)

  • These clinical benefits may be attributable to the increased activation of alveolar macrophages in GM-CSF–treated patients, as determined by increased HLA-DR expression
  • Inhaled GM-CSF did not trigger an influx of proinflammatory neutrophils to the alveolar compartment

4 of the 6 patients receiving GM-CSF recovered and were discharged from the hospital4

HLA-DR=human leukocyte antigen–DR isotype.

Access the full clinical paper

Multiple clinical trials are underway to evaluate GM-CSF for the treatment of COVID-19–associated respiratory illness5-7

These studies will assess the effect of GM-CSF on important clinical outcomes, including restoration of lung function.5-7

Find out more about each trial:

NCT04326920
NCT04400929
NCT04411680

References: 1. Rösler B, Herold S. Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia—a new therapeutic strategy? Mol Cell Pediatr. 2016;3(1):29. 2. Lang FM, Lee KM-C, Teijaro JR, et al. GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches [epub ahead of print]. Nat Rev Immunol. doi:10.1038/s41577-020-0357-7. 3. Paine R III, Standiford TJ, Dechert RE, et al. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit Care Med. 2012;40(1):90-97. 4. Herold S, Hoegner K, Vadász I, et al. Inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome. Am J Respir Crit Care Med. 2014;189(5):609-611. 5. Clinicaltrials.gov. Sargramostim in patients with acute hypoxic respiratory failure due to COVID-19 (SARPAC). Accessed July 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04326920 6. Clinicaltrials.gov. Study of sargramostim in patients with COVID-19 (iLeukPulm). Accessed July 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04411680 7. Clinicaltrials.gov. Using GM-CSF as a host directed therapeutic against COVID-19. Accessed July 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04400929