Inflammasomes form a crucial part of the innate immune system. These are multi-protein oligomer platforms that are composed of intracellular sensors which are coupled with caspase and interleukin activating systems. Nod-like receptor protein (NLRP) 3, and 6 and NLRC4 and AIM2 are the prominent members of the inflammasome family. Inflammasome activation leads to pyroptosis, a process of programmed cell death distinct from apoptosis through activation of Caspase and further downstream targets such as IL-1β and IL-18 leading to activation of inflammatory cascade. Reactive oxygen species (ROS) serves as important inflammasome activating signals. ROS activates inflammasome through mitogen-activated protein kinases (MAPK) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Dysregulation of inflammasome plays a significant role in various pathological processes. Viral infections such as Dengue and Respiratory syncytial virus activate inflammasomes. Crystal compounds in silicosis and gout also activate ROS. In diabetes, inhibition of autophagy with resultant accumulation of dysfunctional mitochondria leads to enhanced ROS production activating inflammasomes. Activation of inflammasomes can be dampened by antioxidants such as SIRT-1. Inflammasome and related cascade could serve as future therapeutic targets for various pathological conditions.

Idiopathic pulmonary fibrosis is a devastating disease characterized by alveolar epithelial cell injury, the accumulation of fibroblasts/ myofibroblasts, and the deposition of extracellular matrix proteins. Lysophosphatidic acid (LPA) signaling through its G proteincoupled receptors is critical for its various biological functions. Recently, LPA and LPA receptor 1 were implicated in lung fibrogenesis. However, the role of other LPA receptors in fibrosis remains unclear. Here, we use a bleomycin-induced pulmonary fibrosis model to investigate the roles of LPA 2 in pulmonary fibrogenesis. In the present study, we found that LPA 2 knockout (Lpar2 2/2 ) mice were protected against bleomycin-induced lung injury, fibrosis, and mortality, compared with wild-type control mice. Furthermore, LPA 2 deficiency attenuated the bleomycin-induced expression of fibronectin (FN), a-smooth muscle actin (a-SMA), and collagen in lung tissue, as well as levels of IL-6, transforming growth factor-b (TGF-b), and total protein in bronchoalveolar lavage fluid. In human lung fibroblasts, the knockdown of LPA 2 attenuated the LPA-induced expression of TGF-b1 and the differentiation of lung fibroblasts to myofibroblasts, resulting in the decreased expression of FN, a-SMA, and collagen, as well as decreased activation of extracellular regulated kinase 1/2, Akt, Smad3, and p38 mitogen-activated protein kinase. Moreover, the knockdown of LPA 2 with small interfering RNA also mitigated the TGF-b1-induced differentiation of lung fibroblasts. In addition, LPA 2 deficiency significantly attenuated the bleomycin-induced apoptosis of alveolar and bronchial epithelial cells in the mouse lung. Together, our data indicate that the knockdown of LPA 2 attenuated bleomycin-induced lung injury and pulmonary fibrosis, and this may be related to an inhibition of the LPA-induced expression of TGF-b and the activation and differentiation of fibroblasts.

These studies suggest that S1PL is a novel endogenous suppressor of pulmonary fibrosis in human IPF and animal models.

We noted a marked increase in cyclooxygenase-2 (Cox2) and the activation of the endoplasmic reticulum (ER) stress pathway in newborn murine lung on exposure to hyperoxia and IFN-g.We soughtto evaluate Cox2-mediated ER stress pathway activation in hyperoxia-induced and IFN-g-mediated injury in developing lungs. We applied in vivo genetic gain-of-function and genetic/chemical inhibition, as well as in vitro lossof-function genetic strategies. Hyperoxia-induced and IFN-g-mediated impaired alveolarization was rescued by Cox2 inhibition, using celecoxib. The use of small interfering RNA against the ER stress pathway mediator, the C/EBP homologous protein (CHOP; also known as growth arrest and DNA damage-inducible gene 153/GADD153), alleviated cell death in alveolar epithelial cells as well as in hyperoxia-induced and IFNg-mediated murine models of bronchopulmonary dysplasia (BPD). In addition, CHOP siRNA also restored alveolarization in the in vivo models. Furthermore, as evidence of clinical relevance, we show increased concentrations of Cox2 and ER stress pathway mediators in human lungs with BPD. Cox2, via CHOP, may significantly contribute to the final common pathway of hyperoxia-induced and IFN-g-mediated injury in developing lungs and human BPD.Keywords: newborn; oxygen; BPD; CHOP; cell deathIn the developing lung, injury attributable to hyperoxic exposure is an important component in the pathogenesis of bronchopulmonary dysplasia (BPD) (1, 2). The immature human lung during the saccular phase is most commonly exposed to such an exogenous insult, and is predisposed to BPD. The final result is a lung phenotype characterized by fewer and larger simplified alveoli (1-4). Hyperoxia-induced lung injury is characterized by an influx of inflammatory cells, along with endothelial and epithelial cell death (5, 6).Cell death is said to be a key initiator of the process of alveolar simplification. The activation of key caspases (3,8,9) and components of the extrinsic/death receptor and intrinsic/ mitochondrial cell death pathways underlies the molecular mechanisms of cell death (5-7). Another cell-death signaling pathway involves the endoplasmic reticulum (ER), which is the site for the folding and assembly of proteins destined for delivery to the extracellular space, plasma membrane, and the exocytic/endocytic compartments (8, 9). When cells are exposed to ER stress, malfolded or unfolded proteins accumulate in the ER lumen, giving rise to a synonymous term, the unfolded protein response (UPR) (8, 9). ER stress is sensed by three ER-resident transmembrane proteins, specifically, inositol-requiring enzyme-1 a (IRE-a), activating transcription factor-6a (ATF6a), and protein kinase regulated by RNA-like ER kinase (PERK), which are freed from binding immunoglobulin protein (BiP; also known as glucoseregulated protein-78, or GRP78) during ER stress (10). Whereas ER stress-induced cell death signaling can occur via multiple pathways, the pathway (i.e., via PERK) that induces transcription of the proapoptotic factor C/EBP homol...