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. 2021 Oct 20;12:733853. doi: 10.3389/fimmu.2021.733853

Figure 1.

Figure 1

Host-directed drugs targeting molecular pathways within lung granulomas. 1) TNF blockers such as soluble TNF receptor 2 fusion protein, etanercept and phosphodiesterase inhibitors (Sildenafil, Cilostazol, CC-3052, and CC-11050) reduce lung inflammation and pulmonary pathology. 2) The antidiabetic drug metformin inhibits mitochondrial respiratory-chain complex 1 and increases AMPK levels. Metformin reduces lung pathology and in Mtb-infected macrophages induces mitochondrial ROS and increases phagolysosome fusion. 3) Histone deacetylase Sirtuin 1 activators (Resveratrol, SRT1720) and Sirtuin 2 inhibitor (AGK2) dampen lung pathology, increase phagolysosome fusion and autophagy. 4) Broad-spectrum metalloproteinase (MMP) inhibitor, Marimastat, enhances anti-tubercular drug delivery and reduces blood vessel leakage. Doxycycline reduces lung lesion sizes. 5) Statins, cholesterol-lowering drugs, reduce lung pathology. In macrophages, statins induce autophagy and increase phagosome maturation. 6) The antioxidant N-acetylcysteine (NAC) decreases pro-inflammatory cytokines, reduces tuberculous granuloma lesions, necrosis, pulmonary infiltrates, and cavity size. 7) Carbamazepine, a sodium channel blocker, decreases lung lesions and induces autophagy in macrophages. 8) Vitamin D and Vitamin A metabolite (all-trans retinoic acid, ATRA), PGE2 and Zileuton, Anakinra and Linezolid induce smaller lung lesions. 9) VEGF blocker (Bevacizumab) reduces angiogenesis and induces functionally better vascularized granulomas. 10) Nonsteroidal anti-inflammatory drugs (Ibuprofen and Aspirin) block cyclooxygenases and reduce lung lesion sizes. 11) The amino acid L-isoleucine decreases pulmonary pathology through the induction of β-defensins. 12) Lactate dehydrogenase A inhibitor (FX11) restricts necrotic lung lesions. 13) The IDO inhibitor, 1-methyl-tryptophan, results in the reorganization of granuloma architecture increasing lymphocyte recruitment into the lesion core. 1-13) All listed HDT candidates reduce mycobacterial burden except for bevacizumab. TNF, Tumor Necrosis Factor; AMPK, AMP-activated protein kinase; Sirtuin, Silent mating type information regulation 2 homolog; ROS, Reactive Oxygen Species; MMP, metalloproteinases; VEGF, Vascular endothelial growth factor; COX, cyclooxygenases; LDHA, Lactate dehydrogenase A; FX11, 7-Benzyl-2;3-dihydroxy-6-methyl-4-propyl-naphthalene-1-carboxylic; IDO, indoleamine 2;3-dioxygenase; ATRA, All-trans retinoic acid; PGE2, Prostaglandin E2. Image of the granuloma structure adapted from reference (3), Nature Publishing Group. Image of the blood vessel structure adapted from reference (8), Wiley Publishing Group (8).