Asthma and poly(ADP-ribose) polymerase inhibition: a new therapeutic approach

Figures & data

Figure 1 Features of PARP knockout mice in asthma at a glance.

Notes: PARP1^−/− and PARP14^−/− knockout mice features. Some of them are common to both enzymes (gray-green area). PARP14^−/− knockout mice show a more specific profile link to a proallergic role of this enzyme in inflammatory airway diseases. However, PARP1^−/− ablation also shows protection in other models of diseases displaying a broader range of functions. *Increased levels were found in T cells derived from PARP1^−/− mice, whereas unchanged or decreased levels were observed in BALF of PARP1^−/− mice after allergen challenge.^18,65 °Data are referred to the frequency of immunoglobulin class recombination of B cell from PARP1^−/− mice.^{66 #}Zhang et al⁶⁸ reported elevated levels of IL17 in PARP1^−/− mice, and Ghonim et al¹⁸ in PARP1-deficient CD4⁺ cells in vitro stimulated. Nasta et al⁶⁷ showed no change in IL17 levels, as well as Ghonim et al¹⁸ in BALF of PARP1^−/− mice. ↓, inhibition/downregulation; ↑, upregulation; ↔, no change.
Abbreviations: AHR, airway hyperresponsiveness; AP-1, activator protein-1; BALF, bronchoalveolar lavage fluid; CCL, chemokine (C–C motif) ligand; CD4⁺, cluster of differentiation 4⁺; ICAMs, intercellular cell adhesion molecules; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; IP-10, interferon-gamma-inducible protein 10; NF-AT, nuclear factor of activated T-cells; NF-κB, nuclear factor κB; PARP, poly(ADP-ribose) polymerase; STAT, signal transducer and activator of transcription; Tfh, T follicular helper; TNF, tumor necrosis factor; Treg, regulatory T cell.

Table 1 PARPs inhibitors and their selectivity for the catalytic domain of different members of PARP family

PARPs inhibitors	Selectivity	References
	Weak, unselective inhibitor except PARP3+	Wahlberg et al^Citation105
	PARP1++ PARP2++ PARP3++	Wahlberg et al ^Citation105
	PARP1, 2+++ PARP3++ PARP4+ PARP14, 16+	Wahlberg et al^Citation105
	PARP1, 3++ PARP2, 4, 10, 14, 15+	Wahlberg et al^Citation105
	Potent and selective PARP1, 2	Lucarini et al^Citation101
	PARP1, 2, 3++++ PARP4+++ PARP12, 15, 16+	Wahlberg et al^Citation105

Notes: The selectivity of several PARPs inhibitors for human PARPs catalytic domain was assessed by DSF. In general, PARP1–4 selective inhibitors have a higher molecular weight and low cLogP values, and they are hydrophilic by exposing an extended polar surface area. On the contrary, unselective PARPs inhibitors are the smaller molecules, with less polar surface area. The selectivity scale is arbitrarily based on the heat map.¹⁰⁵ Two distinct mechanisms of action have been proposed for these drugs: 1) a competitive enzyme inhibition action and 2) a PARP trapping mechanism, which might have a relevant role in PARPs inhibition.³ In vivo, other factors such as different levels of proteins expression, abundance of substrates, and metabolism, to name a few, may influence the activity of PARPs inhibitors.

Abbreviations: 3-ABA, 3-aminobenzamide; 5-AIQ, 5-aminoisoquinolinone; DSF, differential scanning fluorimetry; HYDAMTIQ, hydroxyl-dimethylaminomethyl-thieno[2,3-c]isoquinolin-5(4H)-one; PARP, poly(ADP-ribose) polymerase; PJ-34, N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride; TIQ-A, thieno[2,3-c]isoquinolin-5-one.

Table 2 Effects of PARPs inhibition in asthma models

Mode of PARP inhibition	In vivo models	Findings	References
3-ABA, 20 mg/kg Preallergen challenge	Mice C57BL/6 OVA	↓Inflammatory cell infiltration (BALF/lung) ↓iNOS expression (lung) ↔IgG (serum)	Boulares et al^Citation92
PJ-34, 10 mg/kg Preallergen challenge	Mice Balb/c OVA	↓Neutrophils ↔eosinophils (BALF) ↓Myeloperoxidase activity ↓MIP-2, TNFα, IL12 expression (lung)	Virag et al^Citation93
3-ABA, 10 mg/kg 5-AIQ, 0.5 mg/kg Preallergen challenge	Guinea pigs OVA	↓Severity of cough/dyspnea ↓AHR ↓MPO activity ↓MDA formation ↓Tyrosine nitration (lung) ↓TNFα (BALF) ↓Nitrite level (BALF)	Suzuki et al^Citation94
TIQ-A, 6 mg/kg Preallergen challenge	Mice C57BL/6 OVA	↓Inflammatory cell infiltration ↓IgE (BALF) ↓IL4, IL13, IL5, IL10, GM-CSF (lung) ↓Mucus production (goblet cells)	Oumouna et al^Citation95
TIQ-A, 6 mg/kg Preallergen and postallergen challenge	Mice C57BL/6 OVA	↓AHR ↓IL4, IL5, IL13 ↓IgE (BALF) ↓Mucus production (goblet cells)	Naura et al^Citation96
PJ-34 During sensitization phase, during allergen challenge, and during both challenge and sensitization	Mice Balb/c and C57BL/6 OVA	↓AHR ↓Inflammatory cell infiltration ↓IgE (BALF) ↓IgE (serum) ↓IL4, IL5, IL13 ↓CCL11, CCL17, CCL24 ↓Eosinophils, T cells (lung) ↓Mucus secretion (goblet cells) ↓IL4, IL5, IL13 ↑IFNγ (splenocytes)	Mehrotra et al^Citation78
HYDAMTIQ, 1–10 mg/kg Preallergen challenge	Guinea pigs OVA	↓AHR ↓Appearance and severity of cough ↓Hystamine release (mast cells) ↓TNFα, IL1β, IL5, IL6, IL18 (lung) ↓PGD2 (BALF) ↓MDA, 8-OHdG ↓eMBP, MPO activity (lung) ↑MnSOD (lung) ↓Collagen deposition ↓Smooth muscle layer thickness ↓Goblet cell hyperplasia	Lucarini et al^Citation101
Olaparib, 1–10 mg/kg Postallergen challenge	Mice C57BL/6J OVA	↓Airway cell migration ↓AHR ↓Mucus production (goblet cells) ↓CCL11, IL4, IL5, IL6, IL13, M-CSF ↔IFNγ (BALF) ↓IgE (BALF/serum) ↓CD4^+ T cells ↑Treg cells (spleen)	Ghonim et al^Citation97 (CD4^+ cells)
Olaparib, 5 mg/kg Preallergen challenge	Mice C57BL/6 HDM	↓AHR ↓Overall cellularity in lungs ↓CCL11, IL4, IL5, IL13, IL2, IP-10 (BALF) ↔IFNγ, IL10, IL17 (BALF) ↔CD4^+ T cells ↓Spleen weight, overall number of cells ↑IL17 (serum)	Ghonim et al^Citation18
3-ABA, 40 mg/kg 5-AIQ, 0.5 mg/kg Postallergen challenge	Mice Balb/c HDM	↓Inflammatory cell migration (BALF/lung) ↓STAT6 ↓CCL11 (lung) ↓Collagen deposition ↓goblet cells hyperplasia ↔Airway smooth muscle layer thickness ↔IgE, IgG1, IgG2a (serum) ↔IL4, IL5, IL13 (splenocytes)	Zaffini et al^Citation76

Note: The results obtained on several asthma models with different PARPs inhibitors are summarized.

Abbreviations: 3-ABA, 3-aminobenzamide; AHR, airway hyperresponsiveness; 5-AIQ, 5-aminoisoquinolinone; BALF, bronchoalveolar lavage fluid; CCL, chemokine (C–C motif) ligand; CD4⁺, cluster of differentiation 4⁺; eMBP, eosinophilic major basic protein; GM-CSF, Granulocyte-macrophage colony-stimulating factor; HDM, house dust mite; HYDAMTIQ, hydroxyl-dimethylaminomethyl-thieno[2,3-c]isoquinolin-5(4H)-one; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; IP-10, interferon-gamma-inducible protein 10; M-CSF, macrophage colony-stimulating factor; MDA, malondialdehyde; MIP-2, macrophage inflammatory protein-2; MnSOD, manganese superoxide dismutase activity; MPO, myeloperoxidase activity; OVA, ovalbumin; 8-OHdG, 8-OH-2′-deoxyguanosine; PGD₂, prostaglandin D2; PJ-34, N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride; STAT6, signal transducer and activator of transcription 6; TIQ-A, thieno[2,3-c]isoquinolin-5-one; TNF, tumor necrosis factor.

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