Asthma, acute lung injury (ALI), and chronic obstructive pulmonary disease (COPD) are lung inflammatory disorders with a common outcome, that is, difficulty in breathing. Corticosteroids, a class of potent anti-inflammatory drugs, have shown less success in the treatment/management of these disorders, particularly ALI and COPD; thus, alternative therapies are needed. Poly(ADP-ribose)polymerases (PARPs) are the post-translational modifying enzymes with a primary role in DNA repair. During the last two decades, several studies have reported the critical role played by PARPs in a good of inflammatory disorders. In the current review, the studies that address the role of PARPs in asthma, ALI, and COPD have been discussed. Among the different members of the family, PARP-1 emerges as a key player in the orchestration of lung inflammation in asthma and ALI. In addition, PARP activation seems to be associated with the progression of COPD. Furthermore, PARP-14 seems to play a crucial role in asthma. STAT-6 and GATA-3 are reported to be central players in PARP-1-mediated eosinophilic inflammation in asthma. Interestingly, oxidative stress–PARP-1–NF-κB axis appears to be tightly linked with inflammatory response in all three-lung diseases despite their distinct pathophysiologies. The present review sheds light on PARP-1-regulated factors, which may be common or differential players in asthma/ALI/COPD and put forward our prospective for future studies.

Despite the reported role of poly(ADP‐ribose) polymerase (PARP) in asthma inflammation, its contribution during remodeling is not clearly known. The main aim of the current investigation was to examine the potential of olaparib, a pharmacological inhibitor of PARP against airway remodeling using an ovalbumin (OVA)‐based murine model of chronic asthma. The results demonstrated that post‐challenge olaparib treatment (5 mg/kg i.p., 30 min after OVA exposure) for six weeks (3 days/week) attenuates inflammation, mucus production, and collagen deposition in lungs. Additionally, olaparib blunted the protein expression of STAT‐6 and GATA‐3 considerably along with a modest reduction in p65‐NF‐κB phosphorylation. Furthermore, olaparib normalized the OVA‐induced redox imbalance as reflected by data on reactive oxygen species, malondialdehyde, protein carbonyls, and reduced glutathione/oxidized glutathione ratio. Interestingly, the protection offered by olaparib was further linked with the altered level of NLRP3 inflammasome‐mediated IL‐1β release and consequent expression of its downstream targets matrix metalloproteinase‐9 and transforming growth factor beta. Suppressed collagen deposition in the lungs correlates well with the reduced expression of vimentin upon olaparib treatment. Finally, olaparib restored the expression of histone deacetylase 2, a steroid‐responsive element in asthma. Overall, results suggest that olaparib prevents OVA‐induced airway inflammation as well as remodeling via modulating inflammasome signaling in mice. © 2019 IUBMB Life, 1–11, 2019

Tissue-resident memory CD4 T cells (Trm) are thought to be a major contributor to asthma relapse, but the role of circulatory T cells in asthma exacerbations or to maintaining the population of lung Trm cells is not fully understood. Here, we used a house dust mite allergen-based murine model of asthma relapse, and monitored the development of lung effector/Trm phenotype CD44hiCD62LloCD69+ CD4 T cells. To determine the contribution of circulatory cells, mice were treated with FTY720, to block lymphocyte egress from lymph nodes. Inhibiting the primary migration of circulatory cells to the lungs mitigated the accumulation and expansion of allergen-driven Trm phenotype cells, but subsequent allergen challenges still resulted in strong lung inflammation and Trm cell accumulation. This was blocked if FTY720 was also given at the time of allergen re-exposure, showing that new circulatory cells contributed to this lung memory/effector T cell pool at times well after the initial sensitization. However, once lung-localized Trm cells developed at high frequency, circulatory cells were not required to maintain this population following allergen re-encounter, even though circulatory cells still were major contributors to the overall asthmatic lung inflammatory response. Our results suggest that strategies that target the response of circulatory memory T cells and Trm cells together might be required to strongly inhibit T cell reactivity to airborne allergens and to limit exacerbations of asthma and their reoccurrence, but the contribution of circulatory T cells might vary in long-term asthmatics possessing a large stable Trm cell population in the lungs.

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Lung fibrosis and tissue remodeling are features of chronic diseases such as severe asthma, idiopathic pulmonary fibrosis, and systemic sclerosis. However, fibrosis-targeted therapies are currently limited. We demonstrate in mouse models of allergen- and bleomycin-driven airway inflammation that neutralization of the TNF family cytokine TL1A through Ab blocking or genetic deletion of its receptor DR3 restricted increases in peribronchial smooth muscle mass and accumulation of lung collagen, primary features of remodeling. TL1A was found as a soluble molecule in the airways and expressed on the surface of alveolar macrophages, dendritic cells, innate lymphoid type 2 cells, and subpopulations of lung structural cells. DR3 was found on CD4 T cells, innate lymphoid type 2 cells, macrophages, fibroblasts, and some epithelial cells. Suggesting in part a direct activity on lung structural cells, administration of recombinant TL1A into the naive mouse airways drove remodeling in the absence of other inflammatory stimuli, innate lymphoid cells, and adaptive immunity. Correspondingly, human lung fibroblasts and bronchial epithelial cells were found to express DR3 and responded to TL1A by proliferating and/or producing fibrotic molecules such as collagen and periostin. Reagents that disrupt the interaction of TL1A with DR3 then have the potential to prevent deregulated tissue cell activity in lung diseases that involve fibrosis and remodeling.