Abstract Mesenchymal stromal cells (MSCs) are multipotent cells with well-established regenerative and immunomodulatory properties, making them promising candidates for the treatment of inflammatory diseases. However, the therapeutic effects of MSCs are largely mediated by their secretome, particularly extracellular vesicles (EVs), which deliver bioactive molecules capable of modulating inflammatory responses. We generated an extracellular vesicle-enriched secretome (EVES) from MSCs under scalable, Good Manufacturing Practice (GMP)-compliant conditions and assessed its therapeutic efficacy in diverse disease models, including lung inflammation and kidney injury induced by distinct innate immune stimuli. EVES was isolated from the secretome of umbilical cord blood-derived MSCs cultured in a chemically defined medium. In vitro , EVES significantly and dose-dependently attenuated cytokine release from airway epithelial cells and macrophages stimulated with inflammatory agents such as lipopolysaccharide or reactive particles. In murine models of lung inflammation, EVES reduced neutrophil infiltration and suppressed multiple cytokines and chemokines in a dose-dependent manner. In models of kidney injury, EVES enhanced tubular epithelial cell proliferation, improved renal histology, and markedly reduced tubular necrosis following ischemia-reperfusion injury. Collectively, these findings demonstrate that MSC-derived EVES exhibits robust and broad-spectrum therapeutic activity across multiple disease contexts driven by innate immune activation, supporting its potential as a scalable, cell-free therapeutic platform.

Per- and polyfluoroalkyl substances (PFAS), widely used as durable additives in various consumer products for their water- and oil-repellent properties, persist environmentally and bioaccumulate, raising substantial health concerns. The primary route of human exposure towards PFAS is via contaminated food and drinking water, however, mounting evidence highlights inhalation as additional, critical route of exposure. In particular, inhalation of perfluorooctane sulfonate (PFOS) adversely affects respiratory health through immune disruption, oxidative stress, and impaired barrier function, particularly evident during prenatal exposure. Recent evidence reveals that emerging, anthropogenic PFOS exposure activates innate immune pathways conserved over millions of years of evolution leading to inflammation and tissue injury. PFOS has been shown to trigger the AIM2 inflammasome via mitochondrial damage and DNA release, inducing pyroptosis and IL-1β secretion leading to prolonged inflammation and tissue injury. Beyond inflammasomes, the cGAS/STING axis, which is closely co-regulated with the inflammasome, recognizes ectopic DNA and contributes to PFOS-induced inflammatory responses. Co-exposures to airborne pollutants or infections might additionally amplify these effects, as demonstrated by increased expression of AIM2, cGAS, and STING in lung cells following bacterial or particulate challenges. This commentary highlights the critical need for mechanistic research on PFOS-triggered innate immune signalling and potential harmful co-exposure interactions particularly in the lung to better assess health risks and inform regulatory policies for these persistent environmental contaminants.

Detecting cytoplasmic or extracellular DNA from host or pathogen origin by DNA sensor cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggers immune responses with secretion of type I interferons and inflammatory cytokines. However, STING agonists function as type-2 adjuvant promoting allergic asthma. Here, we asked how cGAS/STING signaling pathway influences allergen-induced type-2 immune responses in models of allergic airway diseases induced by birch pollen extract, house dust mite, or ovalbumin plus Alum. We report increased extracellular dsDNA in the airways, together with cGAS and STING gene expression, following allergen challenge in these models, correlating dsDNA and type-2 cytokine IL-4, IL-5, and IL-13 release. Allergen-induced type-2 immune responses were reduced in cGAS- or STING-deficient mice. Further, blocking cGAS function with the specific inhibitor RU.521 protected mice from birch pollen allergen-induced airway inflammation and type-2 immune responses. Thus, DNA sensing by cGAS contributes to type-2 immune responses and may represent a therapeutic target for allergic lung inflammation.

During maternity mothers undergo an immune pivot to a type 2 immune phenotype which is independent of any antigen experience. In this study we present this maternal Type 2 immunity as a key enabler of optimal maternally-driven microchimeric transfer of immunity to helminth infection in offspring. To demonstrate that maternal type 2 immunity dictates offspring immunity we nursed wildtype (WT) offspring on WT or IL-4Rα-/- foster mothers. WT offspring nursed on IL-4Ra-/- mothers acquired a reduced type 2 immune signature compared to WT offspring nursed on WT mothers. This demonstrated maternal IL-4Rα imprints type 2 immunity in offspring. This increased type 2 immunity in offspring related to a maternal IL-4Rα dependent increased frequency of maternal microchimeric cells (MMc) being detected in offspring. Higher worm burdens were detected in offspring nursed on IL-4Rα-/- mothers, demonstrating that an antigen independent promotion of maternal type 2 immunity provides offspring with protective immunity against a helminth infection. To establish the contribution of increased MMc in offspring nursed on WT mothers in the control of infection, we undertook an antibody mediated depletion of MMc cells in WT offspring. This MMc depletion impaired the control of infection and reduced the magnitude of offspring type 2 immune response against a helminth infection. These findings present antigen independent maternal IL-4Rα driven type 2 immunity during pregnancy as critical for imparting a profound immune influence via MMc on offspring immunity to infection. ### Competing Interest Statement The authors have declared no competing interest.

Psoriasis is a chronic inflammatory skin disorder characterized by aberrant keratinocyte proliferation and immune cell infiltration with upregulation of inflammatory cytokines. Here, we examined the contribution of HCAR2 encoding for the short-chain fatty acid receptor GPR109A. Human and mouse RNA sequencing public datasets reveal elevated HCAR2 gene expression in psoriatic as compared with healthy skin, both in keratinocytes and myeloid cells. Immunostaining and flow cytometry of imiquimod-induced psoriatic-like lesions in Hcar2-mRFP reporter mice showed increased GPR109A expression by keratinocytes and inflammatory cells. GPR109A-deficient mice demonstrated a more severe imiquimod-induced psoriasis-like response than wild-type mice, with exacerbated epidermal hyperplasia, dermal inflammatory cell infiltration, and increased inflammatory mediators myeloperoxidase, CXCL5, LCN2, interleukin (IL)-1β, IL-6, IL-23, and IL-17A. Conversely, topical administration of sodium butyrate reduced imiquimod-induced skin inflammation in wild-type mice, but not in GPR109A-deficient mice. Mechanistically, GPR109A agonist butyrate inhibits histone deacetylase 3, thus inhibiting IL-1β and the inflammatory IL-1β/IL-23/IL-17A axis in imiquimod-induced skin inflammation. Therefore, GPR109A may have a protective role in psoriasis pathogenesis, supporting a potential therapeutic benefit of sodium butyrate administration or other GPR109A agonists for treating psoriasis.

Exposure to ambient Ozone (O3) air pollution directly causes by its oxidative properties, respiratory epithelial cell injury, and cell death, which promote inflammation and hyperreactivity, posing a significant public health concern. Recent clinical and experimental studies have made strides in elucidating the mechanisms underlying O3-induced epithelial cell injury, inflammation, and airway hyperreactivity, which are discussed herein. The current data suggest that O3-induced oxidative stress is a central event-inducing oxeiptotic cell death pathway. O3-induced epithelial barrier damage and cell death, triggering the release of alarmins and damage-associated molecular patterns (DAMPs), with subsequent endogenous activation of Toll-like receptors (TLRs), DNA sensing pathways, and inflammasomes, activating interleukin-1-Myd88 inflammatory pathway with the production of a range of chemokines and cytokines. This cascade orchestrates lung tissue-resident cell activation in response to O3 in leukocyte and non-leukocyte populations, driving sterile innate immune response. Chronic inflammatory response to O3, by repeated exposures, supports a mixed phenotype combining asthma and emphysema, in which their exacerbation by other particulate pollutants potentially culminates in respiratory failure. We use data from lung single-cell transcriptomics to map genes of O3-damage sensing and signaling pathways to lung cells and thereby highlight potential hotspots of O3 responses. Deeper insights into these pathological pathways might be helpful for the identification of novel therapeutic targets and strategies.

The colonic epithelium is a key interface between the gut microbiota and the host. How microbiota-derived signals influence epithelial cell identity and function remains incompletely understood. Here, we used single-cell transcriptomics, antibiotic-mediated microbiota depletion, germ-free mice and colonization experiments in mice to uncover cell-type-specific responses to microbiota changes, highlighting changes in the cell composition and functional diversities in enterocytes. Our analysis demonstrates that the microbiota control the absorptive profile of the colon epithelial cells and reveals non-canonical inter-crypt goblet cells as microbiota-responsive constituents that combine absorptive and secretory features and whose abundance is regulated by the gut microbiota. We found that their number is suppressed through the short-chain fatty acid butyrate and its receptor GPR109A. Analysis in mouse and humans indicates that the expansion of this hybrid population increases with age and that this expansion is driven by microbiome changes. Our work reveals a previously unrecognized level of epithelial plasticity driven by microbial triggers and highlights butyrate, acting as a signaling molecule that shapes the colon micro-anatomy.

Confronting post-stroke neural inflammation is regarded as a promising therapeutic strategy for cerebral ischemia. Macrophage inflammasome activation plays a vital role in driving neural inflammation, and thus directly impacts stroke outcomes. Micheliolide (MCL), a newly discovered modifier of macrophage function, mechanistically suppresses NLRP3 macrophage signaling. The purpose of the present study was to evaluate the role of inflammasome suppression in MCL-based treatment for stroke. Decreased lesion volumes and improved neurological function in mice receiving MCL treatment were measured at both 3- and 14- day intervals after stroke. PKM2 (Pyruvate Kinase M2) was identified as the direct target of MCL that was found to efficiently suppress inflammasome activation and downregulate NF-κB (NLR family pyrin domain containing 3) signaling. P65 (subunit of NF-κB) binding of PKM2 increases during inflammasome induction and MCL treatment interfered with this interaction. In conclusion, MCL interferes with the PKM2-NF-κB interaction during inflammasome activation and ameliorates post-stroke inflammation, demonstrating its potential in acute ischemic stroke treatment.

Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as the senescence-associated secretory phenotype (SASP). Here, we present evidence that the inflammasome sensor, NLRP1, is a key mediator of senescence induced by irradiation both in vitro and in vivo. The NLRP1 inflammasome promotes senescence by regulating the expression of p16, p21, p53, and SASP in Gasdermin D (GSDMD)-dependent manner as these responses are reduced in conditions of NLRP1 insufficiency or GSDMD inhibition. Mechanistically, the NLRP1 inflammasome is activated downstream of the cytosolic DNA sensor cGMP-AMP (cGAMP) synthase (cGAS) in response to genomic damage. These findings provide a rationale for inhibiting the NLRP1 inflammasome-GSDMD axis to treat senescence-driven disorders.

IntroductionCystic fibrosis is a genetic disorder associated with mutations in the Cftr gene, resulting in the production of thick and sticky mucus that can lead to various health complications, primarily affecting the respiratory and digestive systems. Pseudomonas aeruginosa and Aspergillus fumigatus are frequently identified microorganisms in cystic fibrosis (CF) patients. Superinfection by A. fumigatus in patients already colonized by P. aeruginosa causes hypersecretion of the inflammasome-dependent cytokine IL-1β. Unfortunately, high IL-1β release contributes to pulmonary damage in CF patients and decreases lung functions. The detrimental consequences of inflammasome overactivation pose a significant threat to CF patients. Therefore, more studies are needed to fully understand the complex interactions between inflammasomes, bacterial and fungal superinfections, and inflammation in CF.MethodsThe regulation of the inflammasome is studied in vitro during the superinfection by A. fumigatus of macrophages, derived from mice bone marrow and bronchoalveolar lavage, which are infected by the bacterium P. aeruginosa. The activation of the inflammasome is assessed through the analysis of caspase-1 protein cleavage, secretion of the cytokine IL-1β, and induction of cell death (pyroptosis) in infected and control macrophages. To decipher the molecular mechanisms enabling the overactivation of the inflammasome during a bacterial-fungal superinfection, wild-type and transgenic macrophages deleted in immune response and inflammasome signaling pathways, as well as inhibitors, have been used. We also explored the implication of the CFTR protein in inflammasome activation during the superinfection by using Cftr-/- and ΔF508d/d macrophages. Mutant bacterial and aspergillus strains are also employed to characterize the bacterial and fungal patterns involved in this inflammasome overactivation.ResultsIn our study, primary infection with P. aeruginosa showed a potentiation of macrophages allowing the overactivation of the inflammasome in response to a secondary infection with A. fumigatus. Indeed, fungal superinfection of these cells potentiated by the bacterium leads to greater NLRP3 inflammasome, caspases -1 and -8 activation, and heightened secretion of IL-1β. Results show that overactivation of the inflammasome during fungal superinfection is specific to a primary infection with the bacterium P. aeruginosa. The involvement of Cftr gene mutations in inflammasome activation during superinfection appears to depend on the mutation class. Different pathogen-associated molecular patterns (PAMPs) of P. aeruginosa and A. fumigatus are involved in this mechanism, such as type IV pili, flagellin, type II and type III secretion systems of P. aeruginosa, and galactosaminogalactan of A. fumigatus.ConclusionA primary infection with P. aeruginosa results in the potentiation of macrophages, enabling the overactivation of the inflammasome and an excessive secretion of IL-1β in response to a secondary infection by A. fumigatus. This could explain the worsening of pulmonary functions in co-infected patients. Results regarding a specific inflammasome response during superinfection based on Cftr mutations need to be confirmed. Overall, studying the immune response triggered by this interplay between bacteria and fungus in cystic fibrosis is crucial and further investigations are necessary.

Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal interstitial lung disease (ILD) of unknown origin, characterized by limited treatment efficacy and a fibroproliferative nature. It is marked by excessive extracellular matrix deposition in the pulmonary parenchyma, leading to progressive lung volume decline and impaired gas exchange. The chemokine system, a network of proteins involved in cellular communication with diverse biological functions, plays a crucial role in various respiratory diseases. Chemokine receptors trigger the activation, proliferation, and migration of lung-resident cells, including pneumocytes, endothelial cells, alveolar macrophages, and fibroblasts. Around 50 chemokines can potentially interact with 20 receptors, expressed by both leukocytes and non-leukocytes such as tissue parenchyma cells, contributing to processes such as leukocyte mobilization from the bone marrow, recirculation through lymphoid organs, and tissue influx during inflammation or immune response. This narrative review explores the complexity of the chemokine system in the context of IPF and the bleomycin-induced lung fibrosis mouse model. The goal is to identify specific chemokines and receptors as potential therapeutic targets. Recent progress in understanding the role of the chemokine system during IPF, using experimental models and molecular diagnosis, underscores the complex nature of this system in the context of the disease. Despite advances in experimental models and molecular diagnostics, discovering an effective therapy for IPF remains a significant challenge in both medicine and pharmacology. This work delves into microarray results from lung samples of IPF patients and murine samples at different stages of bleomycin-induced pulmonary fibrosis. By discussing common pathways identified in both IPF and the experimental model, we aim to shed light on potential targets for therapeutic intervention. Dysregulation caused by abnormal chemokine levels observed in IPF lungs may activate multiple targets, suggesting that chemokine signaling plays a central role in maintaining or perpetuating lung fibrogenesis. The highlighted chemokine axes (CCL8-CCR2, CCL19/CCL21-CCR7, CXCL9-CXCR3, CCL3/CCL4/CCL5-CCR5, and CCL20-CCR6) present promising opportunities for advancing IPF treatment research and uncovering new pharmacological targets within the chemokine system.

Environmental air pollutants including ozone cause severe irritation and respiratory diseases. Here, we report that 6week's ozone exposure in mice (1.5ppm, twice weekly) causes airway hyperreactivity, eosinophil and neutrophil recruitment, Th2 immune response, respiratory barrier disruption with inflammation, fibrosis and emphysema reminiscent of COPD, more rapidly than cigarette smoke exposure. This model features important aspects of asthma-COPD overlap syndrome (ACOS) as recently described in patients. Since Tiotropium (TTP), an anticholinergic receptor antagonist, blocks smooth muscle cell contraction and mucus secretion with a prolonged bronchodilator effect in patients with asthma or COPD, we asked whether its effect is limited to bronchodilation. We report here that Tiotropium not only reduced airways hyperreactivity, but also drastically diminished eosinophil recruitment, Th2 cell response and ozone-induced lung inflammatory pathology including emphysema. Therefore, chronic O3-induced lung pathology in mice mimics ACOS in patients and is attenuated by TTP treatment. The mechanisms of TTP protective effect on respiratory barrier disruption and chronic inflammation need to be further explored.

Inflammatory bowel diseases (IBD) are chronic, incurable pathologies with unknown causes, affecting millions of people. Pediatric-onset IBD, starting before the age of 18 years, are increasing, with more aggressive and extensive features than adult-onset IBD. These differences remain largely unexplained. Intestinal mucosal damage, cell death, DNA release from nuclear, mitochondrial, or microbiota sources, and DNA-sensing activating the cGAS-STING pathway may contribute to disease evolution. Increased colonic cGAS and STING are increasingly reported in experimental and human IBD. However, limited knowledge of the mechanisms involved hinders the development of new therapeutic options. Here, we discuss recent advances and unresolved questions regarding DNA release, DNA sensor activation, and the role and therapeutic potential of the cGAS-STING pathway in inflammatory colitis.

AbstractRationaleElevated levels of CD11c+ myeloid cells are observed in various pulmonary disorders, including Idiopathic Pulmonary Fibrosis (IPF). Dendritic cells (DCs) and macrophages (MΦ) are critical antigen‐presenting cells (APCs) that direct adaptive immunity. However, the role of CD11c+ myeloid cells in lung extracellular matrix (ECM) accumulation and pulmonary fibrosis is poorly understood.ObjectiveWe aimed to investigate the impact of depleting CD11c+ myeloid cells, including DCs and macrophages, during bleomycin‐induced pulmonary fibrosis in mice.MethodsWe used a diphtheria toxin (DTx) receptor (DTR) transgenic mouse model (CD11c‐DTR‐Tg) to deplete CD11c+ myeloid cells through two methods: Systemic Depletion (SD) via intraperitoneal injection (i.p.) and local depletion (LD) via intranasal instillation (i.n.). We then assessed the effects of CD11c+ cell depletion during bleomycin‐induced lung inflammation and fibrosis.ResultsFourteen days after bleomycin instillation, there was a progressive accumulation of myeloid cells, specifically F4/80‐MHCII+CD11c+ DCs and F4/80 + MHCII+CD11c+ MΦ, preceding mortality and pulmonary fibrosis. Systemic depletion of CD11c+ DCs and MΦ via i.p. DTx administration in CD11c‐DTR‐Tg mice protected against bleomycin‐induced mortality and pulmonary fibrosis compared to wild‐type (WT) mice. Systemic depletion reduced myeloid cells, airway inflammation (total leukocytes, neutrophils, and CD4+ lymphocytes in bronchoalveolar lavage (BAL), inflammatory and fibrogenic mediators, and fibrosis‐related mRNAs (Collagen‐1α1 and α‐SMA). Increased anti‐inflammatory cytokine IL‐10 and CXCL9 levels were observed, resulting in lower lung hydroxyproline content and Ashcroft fibrosis score. Conversely, local depletion of CD11c+ cells increased mortality by acute leukocyte influx (predominantly neutrophils, DCs, and MΦ in BAL) correlated to IL‐1β, with lung hyper‐inflammation and early fibrosis development.ConclusionSystemic depletion of CD11c+ cells confers protection against inflammation and fibrosis induced by Bleomycin, underscoring the significance of myeloid cells expressing F4/80‐MHCII+CD11c+ DCs and F4/80 + MHCII+CD11c+ MΦ orchestrating the inflammatory milieu within the lungs, potentially as a source of cytokines sustaining pulmonary chronic inflammation leading to progressive fibrosis and mortality.

BACKGROUND:Severe refractory, neutrophilic asthma remains an unsolved clinical problem. STING agonists induce a neutrophilic response in the airways, suggesting that STING activation may contribute to the triggering of neutrophilic exacerbations. We aim to determine whether STING-induced neutrophilic lung inflammation mimics severe asthma. METHODS:We developed new models of neutrophilic lung inflammation induced by house dust mite (HDM) plus STING agonists diamidobenzimidazole (diABZI) or cGAMP in wild-type, and conditional-STING-deficient mice. We measured DNA damage, cell death, NETs, cGAS/STING pathway activation by immunoblots, N1/N2 balance by flow cytometry, lung function by plethysmography, and Th1/Th2 cytokines by multiplex. We evaluated diABZI effects on human airway epithelial cells from healthy or patients with asthma, and validated the results by transcriptomic analyses of rhinovirus infected healthy controls vs patients with asthma. RESULTS:DiABZI administration during HDM challenge increased airway hyperresponsiveness, neutrophil recruitment with prominent NOS2+ARG1- type 1 neutrophils, protein extravasation, cell death by PANoptosis, NETs formation, extracellular dsDNA release, DNA sensors activation, IFNγ, IL-6 and CXCL10 release. Functionally, STING agonists exacerbated airway hyperresponsiveness. DiABZI caused DNA and epithelial barrier damage, STING pathway activation in human airway epithelial cells exposed to HDM, in line with DNA-sensing and PANoptosis pathways upregulation and tight-junction downregulation induced by rhinovirus challenge in patients with asthma. CONCLUSIONS:Our study identifies that triggering STING in the context of asthma induces cell death by PANoptosis, fueling the flame of inflammation through a mixed Th1/Th2 immune response recapitulating the features of severe asthma with a prognostic signature of type 1 neutrophils.

Psoriasis is a chronic and recurrent inflammatory skin disease characterized by abnormal proliferation and differentiation of keratinocytes and activation of immune cells. However, the molecular driver that triggers this immune response in psoriatic skin remains unclear. The inflammation-related gene absent in melanoma 2 (AIM2) was identified as a susceptibility gene/locus associated with psoriasis. In this study, we investigated the role of AIM2 in the pathophysiology of psoriasis. We found elevated levels of mitochondrial DNA in patients with psoriasis, along with high expression of AIM2 in both the human psoriatic epidermis and a mouse model of psoriasis induced by topical imiquimod (IMQ) application. Genetic ablation of AIM2 reduced the development of IMQ-induced psoriasis by decreasing the production of type 3 cytokines (such as IL-17A and IL-23) and infiltration of immune cells into the inflammatory site. Furthermore, we demonstrate that IL-17A induced AIM2 expression in keratinocytes. Finally, the genetic absence of inflammasome components downstream AIM2, ASC, and caspase-1 alleviated IMQ-induced skin inflammation. Collectively, our data show that AIM2 is involved in developing psoriasis through its canonical activation.

IntroductionGround-level ozone is an important gaseous constituent of air pollution that contributes to lung disease progression and mortality. Ozone exposure in mice causes pulmonary inflammation evolving into lung emphysema and/or fibrotic patterns but the mechanisms are not well understood [1]. We investigated the role of the poorly characterized innate receptor nucleotide-binding domain and leucine-rich repeat containing protein 6 (NLRP6) involved in inflammasome scaffold [2], in ozone exposure-induced in the context of immunogenic cell death [3].MethodsUsing a chronic ozone exposure model of chronic obstructive pulmonary disease (COPD) in mice, we investigated the role of the NLRP6 receptor in pulmonary inflammation, emphysema and fibrosis by exposing wild-type, Nlrp6 deficient mice and mice deficient for Nlrp6 specifically in lung epithelial cells. In addition, we analyzed NLRP6 expression in lung using NLRP6 FLAG-tagged mice. NLRP6-dependent expression and/or activation of proteins characteristic of immunological cell deaths such as pyroptosis, apoptosis and necroptosis were analyzed by western blotting and immunofluorescence.ResultsWe observed that mouse chronic ozone exposure increased NLRP6 expression in bronchial and alveolar epithelial cells and in a lesser extend in airway macrophages. Interestingly Nlrp6 deficiency dampened pulmonary inflammation and alveolar damage with reduced neutrophil and eosinophil influxes, attenuated chemokine/cytokine and remodeling factor production, collagen deposition and lung fibrosis. Chronic ozone-induced a loss of alveolar type 1 pneumocytes that was attenuated in Nlrp6 deficient mice. Mechanistically, we report that chronic ozone exposure promoted NLRP6-dependent caspase-1, caspase-11 and gasdermin D activation in alveolar type 1 pneumocytes. Chronic ozone exposure also induced NLRP6-dependent expression of apoptotic and necroptotic markers in lung tissue.ConclusionWe identified NLRP6 as a new innate sensor of chronic ozone-induced lung injury promoting pulmonary inflammation leading to emphysema and fibrosis in mice. Our results suggest that chronic ozone induces pulmonary inflammation through NLRP6 inflammasome-dependent pyroptosis and necroptosis of alveolar type 1 pneumocytes. Understanding the mechanisms of pollutant-induced alveolar cell death, lung inflammation and repair might help fight COPD and lung fibrosis.