Sex Steroids Effects on Asthma: A Network Perspective of Immune and Airway Cells

Abstract

A multitude of evidence has suggested the differential incidence, prevalence and severity of asthma between males and females. A compilation of recent literature recognized sex differences as a significant non-modifiable risk factor in asthma pathogenesis. Understanding the cellular and mechanistic basis of sex differences remains complex and the pivotal point of this ever elusive quest, which remains to be clarified in the current scenario. Sex steroids are an integral part of human development and evolution while also playing a critical role in the conditioning of the immune system and thereby influencing the function of peripheral organs. Classical perspectives suggest a pre-defined effect of sex steroids, generalizing estrogens popularly under the “estrogen paradox” due to conflicting reports associating estrogen with a pro- and anti-inflammatory role. On the other hand, androgens are classified as “anti-inflammatory,” serving a protective role in mitigating inflammation. Although considered mainstream and simplistic, this observation remains valid for numerous reasons, as elaborated in the current review. Women appear immune-favored with stronger and more responsive immune elements than men. However, the remarkable female predominance of diverse autoimmune and allergic diseases contradicts this observation suggesting that hormonal differences between the sexes might modulate the normal and dysfunctional regulation of the immune system. This review illustrates the potential relationship between key elements of the immune cell system and their interplay with sex steroids, relevant to structural cells in the pathophysiology of asthma and many other lung diseases. Here, we discuss established and emerging paradigms in the clarification of observed sex differences in asthma in the context of the immune system, which will deepen our understanding of asthma etiopathology.

Kisspeptin regulates airway hyperresponsiveness and remodeling in a mouse model of asthma

“…Asthma is a heterogeneous disorder of the airways mainly associated with chronic airway inflammation, reduced lung functions, tissue remodeling, and AHR [3,8,9,11,26,27]. Several studies have investigated the causative factors as well as the underlying mechanisms responsible for airway inflammation, revealing a broad spectrum of variables [2,7,39]. In contrast, few studies have focused on airway remodeling associated with ASM, which results in chronic airway obstructive changes.…”

“…In contrast, few studies have focused on airway remodeling associated with ASM, which results in chronic airway obstructive changes. Here, the ASM is very crucial, considering its role in controlling the secretion of inflammatory cytokines, extracellular matrix (ECM)/remodeling, and other growth mediators [7,40,41]. Kisspeptins (Kp) belong to a family of neuropeptides and originate from a common precursor, preprokisspeptin, to produce smaller amidated cleaved peptides of different amino acid chain lengths: Kp-10, Kp-13, Kp-14, and Kp-54 [14,16,17,42].…”

“…Multiple lines of evidence support that during severe lung inflammation, activation of numerous inflammatory/structural cells occurs, and each secretes cytokines or chemokines to modulate lung structure and function [7,56,57]. These effects are most likely regulated by the release of inflammatory cytokines from different effector T cells such as Th1/Th2 and Th17.…”

“…In contrast, few studies have focused on airway remodeling associated with ASM, which results in chronic airway obstructive changes. Here, the ASM is very crucial, considering its role in controlling the secretion of inflammatory cytokines, extracellular matrix (ECM)/remodeling, and other growth mediators [7,40,41].…”

“…Asthma is a common chronic airway disorder resulting as a consequence of airway inflammation, hyperreactivity, and remodeling, affecting almost 300 million people worldwide [1][2][3][4]. Factors such as sex, age, disease status, and smoking play critical roles in exacerbating asthma [5][6][7]. Asthma may affect people of any age, although it is more common in females than males, as outlined by multiple studies [8][9][10][11].…”