The Acid-Base Balance and Gender in Inflammation: A Mini-Review

Abstract

In humans, acid-base balance is crucial to cell homeostasis. Acidosis is observed in numerous inflammatory processes, primarily acute conditions such as sepsis, trauma, or acute respiratory distress where females tend to exhibit better prognosis compared with males. The mechanisms underlying these gender-dependent differences are multiple, probably involving hormonal and genetic factors, particularly the X chromosome. Although pH influences multiple immunological functions, gender differences in acid-base balance have been poorly investigated. In this review, we provide an update on gender differences in human susceptibility to inflammatory diseases. We additionally discuss the potential impact of acid-base balance on the gender bias of the inflammatory response in view of our recent observation that girls present higher neutrophilic inflammation and lower pH with a trend toward better prognosis in severe sepsis. We also highlight the potent role played by endothelial cells in gender differences of inflammation through activation of proton-sensing G protein-coupled receptors.

Keywords: acid–base balance; endothelial cells; gender differences; homeostatic balance; inflammation; mechanisms of inflammatory cascade; monocytes; neutrophils.

Figure 1

Protein kinases (circled in red) encoded by X-linked genes and involved in the TLR4 signaling pathway, adapted from the study by Akira et al. (22). An example of TLR4 signaling pathways is shown to highlight the implication of key X chromosome-linked kinases in the triggering of the inflammatory response. AP1, activator protein 1; BTK, Bruton’s tyrosine kinase; c/EBPβ, CCAAT/enhancer-binding protein β; ECSIT, evolutionary-conserved signaling intermediate in Toll pathway; ERK, extracellular signal-regulated MAP kinase; IKK, IκB kinase; IκB, inhibitor kappa B; IRAK, interleukin-1 receptor-associated kinase; JNK, c-Jun N-terminal kinase; MAL, myelin and lymphocyte; MAP, mitogen-activated protein; MD2, lymphocyte 96 antigen; MEKK, MAP/ERK kinase kinase; MKK, MAP kinase kinase; MSK, mitogen- and stress-activated kinase; MYD88, myeloid differentiation primary response 88; NEMO, NF-κB essential modulator; NF-κB, nuclear factor kappa B; p38, p38 MAP kinase; p50, NF-κB subunit 1; p65, NF-κB subunit 3 or RELA, v-rel avian reticuloendotheliosis viral oncogene homolog A; RIP2, receptor interacting protein-2; TAB, TAK1-binding protein; TAK, TGF-β-activated kinase; TIR, Toll/interleukin-1 receptor; TRAF, tumor necrosis factor receptor-associated factor; TRAM, translocating chain-associating membrane; TRIAD3/RNF216, ring finger protein 216; TRIF, TIR-domain-containing adapter-inducing interferon-β; TOLLIP, Toll interacting protein; UBC13, ubiquitin-conjugating enzyme 13; UEV1A, ubiquitin-conjugating enzyme variant 1A.