Neutrophils and IL-1α Regulate Surfactant Homeostasis during Cigarette Smoking

Abstract

Cigarette smoke exposure induces inflammation marked by rapid and sustained neutrophil infiltration, IL-1α, release and altered surfactant homeostasis. However, the extent to which neutrophils and IL-1α contribute to the maintenance of pulmonary surfactant homeostasis is not well understood. We sought to investigate whether neutrophils play a role in surfactant clearance as well as the effect of neutrophil depletion and IL-1α blockade on the response to cigarette smoke exposure. In vitro and in vivo administration of fluorescently labeled surfactant phosphatidylcholine was used to assess internalization of surfactant by lung neutrophils and macrophages during or following cigarette smoke exposure in mice. We also depleted neutrophils using anti–Ly-6G or anti–Gr-1 Abs, or we neutralized IL-1α using a blocking Ab to determine their respective roles in regulating surfactant homeostasis during cigarette smoke exposure. We observed that neutrophils actively internalize labeled surfactant both in vitro and in vivo and that IL-1α is required for smoke-induced elevation of surfactant protein (SP)–A and SP-D levels. Neutrophil depletion during cigarette smoke exposure led to a further increase in SP-A levels in the bronchoalveolar lavage and increased IL-1α, CCL2, GM-CSF, and G-CSF release. Finally, macrophage expression of Mmp12, a protease linked to emphysema, was increased in neutrophil-depleted groups and decreased following IL-1α blockade. Taken together, our results indicate that neutrophils and IL-1α signaling are actively involved in surfactant homeostasis and that the absence of neutrophils in the lungs during cigarette smoke exposure leads to an IL-1α–dependent exacerbation of the inflammatory response.

Smoking status impacts treatment efficacy in smoke-induced lung inflammation: A pre-clinical study

“…Many preclinical studies have explored the inhibition of IL-1 signaling in the context of cigarette smoke exposure and COPD models, where inhibition/deletion of IL-1α or its receptor led to reduced pulmonary neutrophilia and cytokine secretion ( Botelho et al, 2011 ; Morissette et al, 2015 ; Milad et al, 2021 ). Positive results from these animal models led to the exploration of IL-1 signaling blockade in COPD patients, though little to no benefit to lung function or exacerbation risk was observed in these trials: e.g., canakinumab and MEDI8968 ( Table 1 ) ( Novartis, 2011 ; Rogliani et al, 2015 ; Calverley et al, 2017 ).…”

“…For instance, there is growing evidence that withdrawal of inhaled corticosteroids leads to more rapid lung function decline compared to steroid naïve patients (Burge et al, 2000;Wise et al, 2000;Qaseem et al, 2011). Nevertheless, few preclinical studies have specifically explored treatment during cessation or the potential rebound effects of treatment washout, where the IL-1α/β signaling blockade preclinical studies mentioned above focused on inhibition throughout cigarette smoke exposure (Botelho et al, 2011;Milad et al, 2021). Furthermore, following re-exposure to cigarette smoke, we observed that anti-IL-1α administration during cigarette smoking disrupted pulmonary adaptation, worsening inflammatory cytokine secretion and affecting pulmonary macrophage phenotype.…”

Revisiting the role of pulmonary surfactant in chronic inflammatory lung diseases and environmental exposure

“…One potential mechanism for the decreased SP-A and SP-D levels following chronic cigarette smoke exposure is that neutrophils recruited to the lungs secrete protease enzymes capable of cleaving and inactivating these proteins [145,146]. Another study, however, found that SP-A and SP-D levels were increased in the BALF of mice acutely exposed to cigarette smoke exposure, an effect which was heightened when neutrophils were depleted [20]. In the lungs of mice exposed to cigarette smoke for just 5 days, chemically modified SP-A can be detected in the lungs [147].…”

“…These phagocytes participate in the clearance and degradation of pulmonary surfactant and this specific activity is tightly controlled, granulocyte-monocyte colony stimulating factor (GM-CSF) being a prime regulator. It has also been suggested that other phagocytes recruited to the lungs following injury or insult, such as neutrophils, may contribute to surfactant homeostasis in the context of pulmonary inflammation [19,20].…”

Air Pollution and the Airways: Lessons from a Century of Human Urbanization

“…Other studies have found similar effects on the airways when exposed to cigarette smoke via a nose-only or via a whole-body system making it important to take into account when comparing studies [62,63]. Milad et al (2021), recently showed that the recruited neutrophils together with IL-1α produced by epithelial cells can regulate the surfactant homeostasis present after exposure to cigarette smoke [64]. However, more research is needed to clearly investigate if neutrophilic inflammation is a cause for COPD or if neutrophils are just reacting to what happens in the airway environment.…”