Exploration of Immunology

Table 1. Impact of small molecules on inflammatory messengers and growth factors in sepsis and severe SARS-CoV-2 infection/COVID-19

Mediator	Sepsis	COVID-19	Lysosomotropic small molecules
TNFα	↑	↑/w/o	Target	↓
IL-1β	↑	↑/w/o	Target	↓
IL-1RA	↑	↑	n.d.	Unknown
IL-2	↑	w/o	-	o
IL-6	↑	↑	Target	↓↓
IL-7	↑	↑	Target	↓
IL-8	↑	↓/↑	n.d.	Unknown
IL-10	↑	↑	Target^°	↑^°
IL-15	↑	↑	-	o
IL-17A	w/o	↑/w/o	-	o
IFN-γ	↓/↑	↑	n.d.	Unknown
TGF-β	↓/w/o	↑	-	o
MCP-1/CCL2	↑	↑	Target	↓^**
CCL4	↑/w/o	w/o	Target	↓↓
CCL5	↑	↑/w/o	-	o
CCL22	-	↑	-	o
PTX3	↑	↑	Target	↓↓
CXCL2	-	-	Target	↓↓
CXCL3	-	-	Target	↓↓
CXCL10	↑	↑	Target	↓↓
C3/C3aR	↓	↑/w/o	Target C3aR	o/↓⁺
C4	↓	w/o	n.d.	Unknown
C5b-C9	↑	↑	n.d.	Unknown
C5a/C5aR	↑	↑	Target C5aR	o/↓⁺
GM-CSF	↓/↑	↓/↑	n.d.	Unknown
ICAM-1	↑	↑	Target	↓
VCAM1	↑	↑	Target	↓^#
PTGS2	-	-	Target	↓^#

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Messenger/growth factor release depends on disease severity in sepsis [47–62] and severe SARS-CoV-2 infection/COVID-19 [3–9, 63–65]: increased (↑), decreased (↓), without (relevant) changes (w/o), (yet) unknown (-). Targets of lysosomotropic small molecules, inhibitors of endolysosomal acidification, and disruptors of lysosomal proton gradients are indicated as: target (Target), no target (-), or not determined (n.d.). Effects on gene expression [messenger RNA (mRNA)] in LPS stimulated human monomac 6 cells are indicated as: increased (↑), decreased (↓), no effect (o). Reference compound for small lysosomotropic molecules: NB 06 [22], plus literature data of fluvoxamine [66]^#, amitriptyline [67]^°, and ambroxol [68]^**. ⁺ determined as C5 mRNA; IFN-γ: interferon-γ; TGF-β: transforming growth factor-β; MCP-1: monocyte chemoattractant protein-1; CCL2: C-C motif chemokine ligand 2; CXCL2: CXC motif chemokine ligand 2; ICAM-1: intercellular adhesion molecule-1; VCAM1: vascular cell adhesion molecule 1; PTGS2: prostaglandin-endoperoxide synthase 2

Declarations

Acknowledgments

We thank Edith Walther for her tremendous technical support in performing elaborate cell experiments and sample preparation in the initial stages of conceptual work. Tremendous support by Petra and Peter Bauer, Davina Miglietta, Lars Kaiser, the staff at Riesling Apotheke (Ellerstadt, Germany), Europa Apotheke, (Bensheim, Germany), and Apotheke im Markt (Heidelberg, Germany) is gratefully acknowledged.

Author contributions

MB conceived the work; MB, OS, RC, and HPD wrote the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Funding from the Institute of Precision Medicine and the Institute for Applied Research (IAF, Furtwangen University, Schwenningen, Germany) is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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