Chronic obstructive pulmonary disease (COPD) is a complex disease whose pathogenesis includes chronic inflammation and is associated with prolonged exposure to harmful particles, especially cigarette smoke. Elevated concentrations of extracellular Hsp70 (eHsp70), which has an immunomodulatory effect, were measured in the blood of patients with COPD. The aim of this study was to examine whether cigarette smoke extract (CSE), eHsp70 and their combinations stimulate the activation of NLRP3 inflammasome and whether they cause pyroptosis and necroptosis, thus contributing to the propagation of inflammation. rhHsp70 protein was used to mimic immunomodulatory action of eHsp70. In vitro models of COPD, and those are NCI-H292, THP-1, NHBE, and MDM cells, were treated for 24 hours with rhHsp70 at concentrations of 0.3, 1, and 3 μg/mL, 2.5, 5 and 15 % CSE and their combinations. Activation of NLRP3 inflammasome and inflammatory response were examined by determining mRNA expression for NLRP3 and IL-1β by quantitative PCR, and by determining the concentration of secreted IL-1β. Cell viability was determined by measuring LDH activity in the media above the cells and their mode of dying was explored by determining the activation and expression of RIPK3 and MLKL (necroptosis) and GSDMD expression (pyroptosis) by Western blot analysis after 2 and 8 h treatments, as well as the already mentioned IL-1β concentration (pyroptosis). It has been shown that gene expression for NLRP3 and IL-1β, as well as IL-1β secretion, were significantly increased in all cells after individual treatments, indicating inflammasome activation and inflammation. Combination treatments were stimulatory in MDM cells, had an inhibitory effect on NCI-H292 and NHBE cells, and had no effect on THP-1 cells in comparison to individual treatments. Lytic cell death has been observed in cell lines (NCI-H292 and THP-1) but not in primary cells (NHBE and MDM). A change in GSDMD expression or activation of RIPK3 and MLKL has not been demonstrated in MDM cells. GSDMD expression was reduced in NCI-H292 and THP-1 cells, but GSDMD-NT was not detected. Activated or phosphorylated forms of RIPK3 and MLKL were detected in NHBE cells, indicating necroptosis or an alternative activation of NLRP3 inflammasome that is thought to be involved in many sterile inflammatory conditions, such as the stable phase of COPD.