Necroptosis has emerged as one of the crucial pathological processes involved in the regulation of cell death and inflammation in chronic obstructive pulmonary disease (COPD). Airway epithelial necroptosis is closely linked to COPD pathogenesis. Necroptotic lung cells can release damage-associated molecular patterns (DAMPs) that can initiate a robust inflammatory response. However, the underlying mechanism of necroptosis in COPD is still not clearly understood. Therefore, we aimed to explore the roles and mechanisms of receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-mediated necroptosis in the regulation of inflammatory responses in COPD to provide insights into RIPK1-inhibitor drug discovery efforts and their therapeutic benefits in COPD.

Emphysema is a progressive disease characterized by irreversible airspace enlargement followed by a decline in lung function. It also causes extrapulmonary effects, such as loss of body mass and cor pulmonale, which are associated with shorter survival and worse clinical outcomes. Ghrelin, a growth-hormone secretagogue, stimulates muscle anabolism, has anti-inflammatory effects, promotes vasodilation, and improves cardiac performance. Therefore, we hypothesized that ghrelin might reduce lung inflammation and remodelling as well as improve lung mechanics and cardiac function in experimental emphysema.
Forty female C57BL/6 mice were randomly assigned into two main groups: control (C) and emphysema (ELA). In the ELA group (n=20), animals received four intratracheal instillations of pancreatic porcine elastase (PPE) at 1-week intervals. C animals (n=20) received saline alone (50 μL) using the same protocol. Two weeks after the last instillation of saline or PPE, C and ELA animals received ghrelin or saline (n=10/group) intraperitoneally (i.p.) daily, during 3 weeks. Dual-energy X-ray absorptiometry (DEXA), echocardiography, lung mechanics, histology, and molecular biology were analysed.
In elastase-induced emphysema, ghrelin treatment decreased alveolar hyperinflation and mean linear intercept, neutrophil infiltration, and collagen fibre content in the alveolar septa and pulmonary vessel wall; increased elastic fibre content; reduced M1-macrophage populations and increased M2 polarization; decreased levels of keratinocyte-derived chemokine (KC, a mouse analogue of interleukin-8), tumour necrosis factor-α, and transforming growth factor-β, but increased interleukin-10 in lung tissue; augmented static lung elastance; reduced arterial pulmonary hypertension and right ventricular hypertrophy on echocardiography; and increased lean mass.
In the elastase-induced emphysema model used herein, ghrelin not only reduced lung damage but also improved cardiac function and increased lean mass. These findings should prompt further studies to evaluate ghrelin as a potential therapy for emphysema.

Left heart diseases (LHD) represent the most prevalent cause of pulmonary hypertension (PH), yet there are still no approved therapies that selectively target the pulmonary circulation in LHD. The increase in pulmonary capillary pressure due to LHD is a triggering event leading to physical and biological alterations of the pulmonary circulation. Acutely, mechanosensitive endothelial dysfunction and increased capillary permeability combined with reduced fluid resorption lead to the development of interstitial and alveolar oedema. From repeated cycles of such capillary stress failure originate more profound changes with pulmonary endothelial dysfunction causing increased basal and reactive pulmonary vascular tone. This contributes to pulmonary vascular remodelling with increased arterial wall thickness, but most prominently, to alveolar wall remodelling characterized by myofibroblasts proliferation with collagen and interstitial matrix deposition. Although protective against acute pulmonary oedema, alveolar wall thickening becomes maladaptive and is responsible for the development of a restrictive lung syndrome and impaired gas exchanges contributing to shortness of breath and PH. Increasing awareness of these processes is unraveling novel pathophysiologic processes that could represent selective therapeutic targets. Thus, the roles of caveolins, of the intermediate myofilament nestin and of endothelial calcium dyshomeostasis were recently evaluated in pre-clinical models. The pathophysiology of PH due to LHD (group II PH) is distinctive from other groups of PH. Therefore, therapies targeting PH due to LHD must be evaluated in that context.

Asthma is associated with structural remodelling processes, including basement membrane thickening, increased vascularity and smooth muscle alterations. It is known that respiratory infections are associated with asthma exacerbation; infections can worsen asthma symptoms and influence susceptibility to asthma onset. How infections affect asthma is not fully elucidated. It is possible that the immune response, due to recurrent infections, leads to the pathogen\'s eradication but also increases bronchial inflammation, which induces airway remodelling in asthmatic subjects. We evaluated how infection affects lung remodelling and inflammatory responses and assessed the impact of antibiotic treatment in a murine model of asthma. Ovalbumin-sensitised BALB/c mice were divided into control, mild and chronic asthmatics. A subset of animals in each group was infected with Streptococcus pneumoniae and was treated with antibiotics. The results show an increase in key lung remodelling factors in mice with chronic asthma, particularly those infected with S. pneumoniae. Notably, antibiotic therapy attenuated these effects. These findings demonstrate for the first time that prompt antibiotic therapy may be useful to reduce lung remodelling progression in infected asthmatic subjects.