Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms, such as wheezing, shortness of breath, chest tightness, and cough, that vary over time and in intensity, together with a variable expiratory airflow limitation ^[1][51]. Asthma is characterized by the chronic inflammation of the pulmonary airways, comprising several pheno-endotypes with distinct clinical features, pathobiological mechanisms, and biomarker expression ^[2][3][52,53]. Its remarkable features are airway hyperresponsiveness (AHR), persistent airway inflammation, and airway remodeling ^[4][54].

Concerning the pathobiology of asthma, inflammation of the lung is primarily characterized by a dichotomy of a preponderant (>50%) type 2-high response—including eosinophilic, allergic, and non-allergic asthma—and a type 2-low response involving a neutrophilic and pauci-granulocytic asthma, if there is no evidence of elevated sputum eosinophils or neutrophils, and if treatments aimed at suppressing eosinophils and neutrophils are ineffective in controlling the symptoms ^[5][55]. In this last endotype, elevated levels of IFN-γ and other cytokines released from Th1, Th17, or type 3 innate lymphoid cells are observed ^[5][6][7][55,56,57]. In most cases, the asthmatic phenotype with a neutrophilic inflammation is associated with the Th17 pathways, increased IL-8 production, and stronger activation of innate immune mechanisms ^[8][58].

In this regard, the pathogenesis of the allergic inflammation of the airways is often due to the excessive activation of Th2 cells together with the deficient suppression of regulatory T cells (Tregs) ^[9][13]. Thus, biological agents targeting specific immune mediators such as type 2 cytokines (IL-4, IL-5, and IL-13) or immunoglobulin E (IgE) have emerged as a safe and effective tailored therapy for severe asthma ^[10][11][59,60]. Wang et al. showed that IGF signaling evolves important functions in asthma physiopathology at different stages, including type 2 high inflammation, eosinophilia, mucus production, bronchial hyperresponsiveness, and lung remodeling ^[12][40]. Interestingly, several studies have shown that mesenchymal stem cells (MSCs) can recover allergic airway inflammation in asthmatic mice ^[13][14][61,62].

The immune suppression mechanism of MSCs in allergic airway disorders is strongly related to Treg expansion and upregulated levels of transforming growth factor-β (TGF-β), and interleukin- (IL-) 10. Many studies also confirmed that MSC-driven immunomodulation is mediated by the reduction of proinflammatory Th1 responses with a concomitant rebalancing of the Th1/Th2 ratio on Th2 ^[15][63]. As widely demonstrated, all these factors are related to IGFBP-6, which is an important mediator of chemotaxis and the immune response ^[16][39].

IGFBP-6 is involved in the pathophysiology of asthma, as demonstrated in different genome-wide association studies, the candidate genes approach, and the genomic expression and linkage analysis which identified over 300 genes associable with asthma pathophysiology, including IGFBP-6 ^[17][12]. Then, IGFBP-6 may be involved in the amelioration of allergic airway inflammation, as its expression was significantly increased in the lung of asthmatic mice following the treatment with adipose-stem-cell-derived extracellular vesicles, a condition normally associated with the suppression of allergic airway inflammation ^[9][13]. All this information may be used to shed light on the basic biology and disease pathogenesis, which will conclusively promote the development of personalized therapies targeting the cause of the underlying disease. Recent studies suggested that inflammation and cytokines are closely related to acute mountain sickness (AMS) ^[18][64], an inflammatory condition originated by a hypoxia-induced hypoxemia reaction with the consequent release of inflammatory mediators that led to over-perfusion and vasodilatation, contributing to the increase of the capillary pressure ^[19][49]. Patients with asthma could develop symptoms of AMS. AMS-resistant individuals have a greater capability to control anti-inflammation damage than AMS-susceptible individuals, as demonstrated by the comparison of their plasma cytokine profiles at low altitudes. IGFBP-6 levels were significantly lower in AMS-susceptible individuals; thus, it may be implicated in predicting AMS susceptibility in low-altitude conditions ^[19][49].

In asthmatic subjects, the primary site for airway inflammation and remodeling is the bronchial tissue ^[20][65]. Specifically, airway remodeling in asthma is pathologically characterized by mucosal hypersecretion and goblet cell metaplasia, a thickening of the subepithelial basement membrane due to an increased deposition of extracellular matrix proteins, airway smooth muscle hyperplasia, and angiogenesis ^[21][22][66,67]. The gene expression profile obtained from asthmatic subjects’ bronchial tissues before and after the treatment with inhaled corticosteroids (ICS) was used to identify genes associated with asthma pathogenesis, together with the original susceptibility genes. Comparing the subjects with allergic asthma and healthy controls in their bronchial biopsies before and following an inhaled corticosteroid (ICS) therapy, 74 genes were found to be differentially expressed. Among differentially expressed genes that control cell growth and proliferation, there is also IGFBP-6, which presented a lower expression in asthmatic patients as compared with healthy controls that was recovered by ICS, providing insights into the pathophysiologic process active in the asthmatic lung and clarifying one of its possible roles in the natural history of asthma ^[23][48].

To summarize, IGFBP-6 levels are significantly higher in asthma after ICS therapy. Therefore, IGFBP-6 may be involved in the amelioration of allergic airway inflammation; thus, enhancing the IGFBP-6 expression might lead to the improvement of current therapies.

IGF and IGFBP expression is deregulated in IPF, a form of chronic interstitial pneumonia depicted by fibrotic alterations heading to alveolar destruction and ongoing obstructive lung disease ^[24][68]. Events that possibly contribute to the final lung fibrosis, such as fibroblast activation and trans-differentiation to a myofibroblast phenotype, increased ECM production and epithelial–mesenchymal transition (EMT), and decreased ECM degradation, designating the IGFBPs’ involvement in the beginning and progression of the fibrosis process ^[25][46].

LAM is characterized by the proliferation of abnormal smooth muscle cells (LAM cells), as well as the formation of nodules in the pulmonary interstitium and multiple cysts throughout the lungs ^[26][69]. It is strongly suggested that the IGF system is involved in the proliferation of LAM cells ^[27][9]. Evaluating the expression of IGFs, IGF1R, and IGFBPs in the lungs of patients with LAM, Valencia et al. demonstrated that IGFBP-6 is localized and can be synthesized by LAM cells and can modulate the effects of the IGFs on LAM cell proliferation ^[27][9]. IGFBP-6 was associated with spindle-shaped LAM cells, a typical LAM neoplastic cell type, and appeared to be involved in their development ^[27][28][9,50].

The patterns of IGFBP-6 localization and expression in LAM strongly suggest that it is involved in the proliferation of LAM cells, modulating the IGF effect on them. Blocking its expression could be revealed as an efficient hormone therapy to regulate the expression of IGFBPs.

CF is a common life-limiting genetic disorder, caused by the mutation of a gene that encodes a chloride-conducting transmembrane channel called the CF transmembrane conductance regulator (CFTR), resulting in the failure of chloride secretion and sodium hyperabsorption with the consequent alteration of the anion transport and mucociliary clearance in the airways ^[29][70]. This functional failure leads to several conditions harmful to the lung, such as viscous mucus retention at the epithelial surface, chronic infection, and, subsequently, a local airway inflammation ^[29][30][70,71]. As a result, CF patients are exposed to the contraction of bacterial lung infections with opportunistic pathogens, associated with chronic inflammation in the CF lung, whose hallmarks are increased levels of neutrophil attraction by chemokines ^[31][72].

The involvement and role that IGF superfamily members and IGFBPs may have in CF lung disease are completely unknown. RWesearchers have recently highlighted that IGFBP-6 may play a direct role in CF-associated inflammation. The basal IGFBP-6 mRNA and protein levels are both upregulated in the bronchial epithelial F508del-CFTR CFBE cells lines and primary nasal epithelial cells (HNE) from three CF patients bearing the most common CF-causing mutation (F508del). Moreover, rwesearchers found that the IGFBP-6 expression was further increased after infection/inflammation stimulation in both the CFBE cell line and HNE cultures. Treatment with a clinically approved anti-inflammatory drug (dimethyl fumarate) significantly reduced the IGFBP-6 mRNA levels in the CFBE cell lines and HNE cultures, suggesting its role in CF inflammation. Moreover, it was demonstrated that IGFBP-6 downregulated the level of pro-inflammatory cytokines in both the CFBE and primary nasal epithelial cells. Lastly, IGFBP-6 treatment did not affect the wild-type and rescued F508del-CFTR protein expression and function, demonstrating its specific role in inflammation regulation ^[32][14].